EP4604947A2 - Compositions and methods for preventing cardiomyopathy - Google Patents

Compositions and methods for preventing cardiomyopathy

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Publication number
EP4604947A2
EP4604947A2 EP23880797.8A EP23880797A EP4604947A2 EP 4604947 A2 EP4604947 A2 EP 4604947A2 EP 23880797 A EP23880797 A EP 23880797A EP 4604947 A2 EP4604947 A2 EP 4604947A2
Authority
EP
European Patent Office
Prior art keywords
usp30
optionally substituted
alkyl
mitophagy
cardiomyopathy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23880797.8A
Other languages
German (de)
French (fr)
Inventor
Nuo SUN
Mingchong YANG
Ruohan ZHANG
Judith KRIGMAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ohio State Innovation Foundation
Original Assignee
Ohio State Innovation Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ohio State Innovation Foundation filed Critical Ohio State Innovation Foundation
Publication of EP4604947A2 publication Critical patent/EP4604947A2/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • cardiomyopathy the heart muscle becomes enlarged, thick, or rigid. In rare cases, the muscle tissue in the heart is replaced with scar tissue. As cardiomyopathy worsens, the heart becomes weaker. It is less able to pump blood through the body and maintain a normal electrical rhythm. This can lead to heart failure or irregular heartbeats called arrhythmias. In turn, heart failure can cause fluid to build up in the lungs, ankles, feet, legs, or abdomen. The weakening of the heart also can cause other complications, such as heart valve problems.
  • the main types of cardiomyopathy are dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular dysplasia.
  • cardiomyopathy can be acquired or inherited, with hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia substantially being inherited disorders. However, in many cases, cardiomyopathy can be induced by other diseases or conditions, or by various toxins or drugs.
  • dilated cardiomyopathy can result from coronary heart disease, heart attack, high blood pressure, diabetes, thyroid disease, viral hepatitis, and HIV; infections, especially viral infections that inflame the heart muscle can result in cardiomyopathy; alcohol, especially in conjunction with a poor diet; complications during the last month of pregnancy or within 5 months of birth; certain Attorney Docket No.103361-086WO1 toxins, such as cobalt; and certain drugs (such as cocaine and amphetamines) and chemotherapeutic drugs (e.g., anthracyclines such as doxorubicin and daunorubicin) and drugs for the treatment of diabetes, which can result in abrupt cardiomyopathic events.
  • drugs such as cocaine and amphetamines
  • chemotherapeutic drugs e.g., anthracyclines such as doxorubicin and daunorubicin
  • the cardiomyopathy can be drug induced cardiomyopathy.
  • the cardiomyopathy can be caused or induced by a drug such as an anthraquinone, an antipsychotic phenothiazine derivate, an arnica herb, arsenic, an amphetamine, an anabolic-androgenic steroids, an azidothymidine, an anagrelide, a catecholamines, cytarabine, clozapine, cobalt, cocaine, chloroquine, a cyclophosphamide, a diazoxide, an anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), ethanol, imatinib, isoproterenol, ephedrine, melarsoprol, methamphetamine, methylphenidate, minoxidil, mitomycin, mitoxantrone, paclit
  • a drug
  • the cardiomyopathy can be caused or induced by an anthracycline. In certain embodiments, the cardiomyopathy can be caused or induced by doxorubicin. In some embodiments, the method can further comprise administering the small molecule USP30 inhibitor in combination with other therapies such as, radiation therapy, surgery, conventional chemotherapy, or with a combination of one or more additional therapies. In certain embodiments, the conventional chemotherapy comprises a Attorney Docket No.103361-086WO1 chemotherapeutic agent inducing cardiomyopathy.
  • the chemotherapeutic agent inducing cardiomyopathy can comprise, for example, an anthracycline (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone).
  • an anthracycline e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone.
  • the cardiomyopathy can be caused or induced by a viral infection, coronary artery disease, or high blood pressure.
  • the cardiomyopathy can be caused or induced by viral infection caused by a virus selected from Coxsackie B and adenovirus, echoviruses, influenza H1N1, Epstein- Barr virus, rubella virus, varicella-zoster virus, mumps virus, measles virus, paroviruses, yellow fever virus, dengue virus, polio virus, rabies virus and the viruses that cause hepatitis A virus and hepatitis C virus, and coronaviruses such as SARS-COV-2.
  • the cardiomyopathy can be caused or induced by a SARS-COV-2 infection (e.g., Covid-19).
  • the USP30 inhibitor can be administered by any suitable route.
  • the USP30 inhibitor can be administered orally, topically, intravenously, subcutaneously, transcutaneous, transdermally, intramuscularly, intradermally, intraventricularly, intracranially, or intraperitoneally.
  • methods of treating cancer in a subject in need thereof that comprise administering to the subject a chemotherapeutic agent and an effective amount of a small molecule USP30 inhibitor to inhibit, decrease, or reduce USP30 activity.
  • the chemotherapeutic agent can comprise an anthracycline (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and/or mitoxantrone).
  • chemotherapeutic regimens for the treatment of cancer can comprise a therapeutically effective amount of a chemotherapeutic agent to treat the cancer and an effective amount of a small molecule USP30 inhibitor to inhibit, decrease, or reduce USP30 activity.
  • the chemotherapeutic agent can comprise an anthracycline (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and/or mitoxantrone).
  • Figures 1A-1D illustrate that a USP30 inhibitor, St-539, promotes mitophagy.
  • Figure 1A shows the analysis of TOM20 ubiquitination, as well as levels of TOM20, TIM23, and TOM40 in the presence or absence of A/O treatment in HeLa cells expressing Parkin or Parkin/Myc-tagged USP30. Shown is one representative western blot from three independent experiments, all providing similar results.
  • Figure 1B shows the chemical structure of ST-539.
  • Figure 1C shows representative immunoblotting for TOM20 TOM40 and TIM23 in HeLa cells expressing Parkin or Parkin/Myc-tagged USP30.
  • FIG. 1D shows representative FACS analysis of AO-induced mitophagy using mt-Keima fluorescence.
  • Cells were treated with A/O for 2h and analyzed by FACS for lysosomal positive mt- Keima (pH4).
  • Prior to A/O treatment cultures were treated with DMSO or ST- 539(3 ⁇ g/ml).
  • Figures 2A-2C show that the inhibition of USP30 by ST-539 requires PINK1 and Parkin.
  • Figure 2B shows the analysis of TOM20 ubiquitination in HeLa cells, HeLa cells expressing YFP-Parkin and PINK1 KO Hela cells expressing YFP-Parkin.
  • Figure 2C shows representative immunoblotting for TOM20 and NDP52 in HeLa cells, HeLa cells expressing YFP-Parkin and PINK1 KO HeLa cells expressing YFP- Parkin or Parkin/Myc-tagged USP30 following A/O treatment for 18h.
  • Prior to A/O treatment cultures were treated with 3 ⁇ g/ml ST-539.
  • Figures 3A-3D show that ST-539 has minimal effect on mitochondrial function in cells.
  • Figure 3A is a bar graph showing the quantification of TMRM signal in Hela-Parkin or HeLa-Parkin/USP30 cells in the presence or absence of ST-539 (ST, 3 or 10 ⁇ g/ml) or FCCP (10 ⁇ M).
  • the intensity of TMRM reflects the level of mitochondrial membrane potential ( ⁇ m). Values are normalized to the vehicle (DMSO) treated samples. Data represent mean ⁇ SD of three independent experiments.
  • Figure 3B shows HeLa-Parkin Attorney Docket No.103361-086WO1 (upper) or HeLa-Parkin/USP30 (lower) cells analyzed using a Seahorse XF96 analyzer. Slightly increased basal respiration and spare respiratory capacity were observed in both cells after ST-539 treatment.
  • Figure 4B provides an assessment of mitophagy using mt-Keima mice. Left, representative confocal images of heart and liver tissue from vehicle or ST-539 (25mg/kg/day for 5 days) treated mt-Keima mice; right, quantification of cardiac and hepatic mitophagy. The emission signal obtained after excitation with the 458-nm laser is shown in green, and that obtained after excitation with the 561-nm laser is shown in red. Individual mouse data points are shown.
  • ST-539 treated hearts exhibited increased levels of LC3-II compared to vehicle treated Attorney Docket No.103361-086WO1 hearts, consistent with augmented cardiac mitophagy following ST-539 treatment.
  • Data are PHDQ ⁇ V ⁇ G ⁇ S ⁇ Figures 8A-8D further illustrate that USP30 inhibition promotes cardiac mitophagy.
  • Figure 9 shows that ST-539 reduces doxorubicin-induced cell death in Human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs). The plot in Figure 9 shows the percent survival of hiPSC-CMs 48 hours after treatment with vehicle (DMSO), doxorubicin, and doxorubicin+ST-539.
  • Figure 10 shows that ST-539 potentiates doxorubicin-induced apoptosis in leukemia.
  • the plot in Figure 10 shows the percent cell viability of Jurkat T cells 48 hours after treatment with ST-539 and doxorubicin, as determined using a Resazurin assay.
  • DETAILED DESCRIPTION A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. Definitions To facilitate understanding of the disclosure set forth herein, a number of terms are defined below. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
  • the use of the terms “a”, “an”, and “the” when used in conjunction with an element may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” Therefore, an element preceded by “a” or “an” does not, without more constraints, preclude the existence of additional identical elements.
  • the use of the term “about” applies to all numeric values, whether or not explicitly indicated. This term generally refers to a range of numbers that one of ordinary skill in the art would consider as a reasonable amount of deviation to the recited numeric values (i.e., having the equivalent function or result).
  • this term can be construed as including a deviation of ⁇ 10 percent of the given numeric value provided such a deviation does not alter the end function or result of the value. Therefore, a value of about 1% can be construed to be a range from 0.9% to 1.1%. Furthermore, a range may be construed to include the start and the end of the range. For example, a range of 10% to 20% (i.e., range of 10%-20%) can includes 10% and also includes 20%, and includes percentages in between 10% and 20%, unless explicitly stated otherwise herein. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value.
  • the terms “may,” “optionally,” and “may optionally” are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur.
  • the statement that a formulation "may include an excipient” is meant to include cases in which the formulation includes an excipient as well as cases in which the formulation does not include an excipient.
  • Administration to a subject includes any route of introducing or delivering to a subject an agent.
  • Administration can be carried out by any suitable route, including oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation, via an implanted reservoir, parenteral (e.g., subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injections or infusion techniques), and the like.
  • parenteral e.g., subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injections or infusion techniques
  • Constant administration means that the compounds are administered at the same point in time or essentially immediately following one another. In the latter case, the two compounds are administered at times sufficiently close that the results observed are indistinguishable from those achieved when the compounds are administered at the same point in time.
  • Systemic administration refers to the introducing or delivering to a subject an agent via a route which introduces or delivers the agent to extensive areas of the subject's body (e.g. greater than 50% of the body), for example through entrance into the circulatory or lymph systems.
  • local administration refers to the introducing or delivery to a subject an agent via a route which introduces or delivers the agent to the area or area immediately adjacent to the point of administration and does not introduce the agent systemically in a therapeutically significant amount.
  • locally administered agents are easily detectable in the local vicinity of the point of administration but are undetectable or detectable at negligible amounts in distal parts of the subject's body.
  • Administration includes self-administration and the administration by another.
  • Attorney Docket No.103361-086WO1 As used here, the terms “beneficial agent” and “active agent” are used interchangeably herein to refer to a chemical compound or composition that has a beneficial biological effect.
  • Beneficial biological effects include both therapeutic effects, i.e., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, i.e., prevention of a disorder or other undesirable physiological condition.
  • the terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, isomers, fragments, analogs, and the like.
  • a “decrease” can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity.
  • a substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed.
  • a decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount.
  • the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant.
  • “Inhibit,” “inhibiting,” and “inhibition” mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level.
  • the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels.
  • “Inactivate”, “inactivating” and “inactivation” means to decrease or eliminate an activity, response, condition, disease, or other biological parameter due to a chemical (covalent bond formation) between the ligand and a its biological target.
  • “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g., tumor growth). It is understood that this Attorney Docket No.103361-086WO1 is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to.
  • “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control.
  • the terms “treating” or “treatment” of a subject includes the administration of a drug to a subject with the purpose of preventing, curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, stabilizing or affecting a disease or disorder, or a symptom of a disease or disorder.
  • the terms “treating” and “treatment” can also refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage.
  • treatment includes the alleviation, in part or in whole, of the symptoms of coronavirus infection (e.g., sore throat, blocked and/or runny nose, cough and/or elevated temperature associated with a common cold).
  • Such treatment may include eradication, or slowing of population growth, of a microbial agent associated with inflammation.
  • prevent or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce.
  • something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed.
  • the terms “prevent” or “suppress” can refer to a treatment that forestalls or slows the onset of a disease or condition or reduced the severity of the disease or condition.
  • a treatment can treat a disease in a subject having symptoms of the disease, it can also prevent or suppress that disease in a subject who has yet to suffer some or all of the symptoms.
  • the term “preventing” a disorder or unwanted physiological event in a subject refers specifically to the prevention of the occurrence of symptoms and/or their underlying cause, wherein the subject may or may not exhibit heightened susceptibility to the disorder or event.
  • Attorney Docket No.103361-086WO1 “prevention” includes reduction in risk of coronavirus infection in patients. However, it will be appreciated that such prevention may not be absolute, i.e., it may not prevent all such patients developing a coronavirus infection, or may only partially prevent an infection in a single individual. As such, the terms “prevention” and “prophylaxis” may be used interchangeably.
  • an “effective amount” of a therapeutic agent is meant a nontoxic but sufficient amount of a beneficial agent to provide the desired effect.
  • the amount of beneficial agent that is “effective” will vary from subject to subject, depending on the age and general condition of the subject, the particular beneficial agent or agents, and the like. Thus, it is not always possible to specify an exact “effective amount”. However, an appropriate “effective’ amount in any subject case may be determined by one of ordinary skill in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an “effective amount” of a beneficial can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts.
  • “Pharmaceutically acceptable carrier” (sometimes referred to as a “carrier”) means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and/or human pharmaceutical or therapeutic use.
  • carrier or “pharmaceutically acceptable carrier” can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil/water or water/oil emulsion) and/or various types of wetting agents.
  • carrier encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as described further herein.
  • pharmaceutically acceptable salt is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable.
  • Salts of the present compounds further include solvates of the compounds and of the compound salts.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of Attorney Docket No.103361-086WO1 acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • pharmacologically active can refer to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
  • a “control” is an alternative subject or sample used in an experiment for comparison purposes.
  • a control can be "positive” or "negative.”
  • a “subject” is meant an individual.
  • the “subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.), and birds.
  • “Subject” can also include a mammal, such as a primate or a human.
  • the subject can be a human or veterinary patient.
  • patient refers to a subject under the treatment of a clinician, e.g., physician.
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • heteroatoms present in a compound or moiety, such as nitrogen can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valency of the heteroatom.
  • substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound (e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substitution means that substitution with an additional group is optional and therefore it is possible for the designated atom to be unsubstituted.
  • the disclosure includes examples where the group is substituted and examples where it is not.
  • alkyl refers to saturated, straight-chained or branched saturated hydrocarbon moieties.
  • C 1 -C 24 (e.g., C 1 -C 22 , C 1 -C 20 , C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, or C1-C4) alkyl groups are intended.
  • alkyl groups include methyl, ethyl, propyl, 1-methyl-ethyl, butyl, 1-methyl- propyl, 2-methyl-propyl, 1,1-dimethyl-ethyl, pentyl, 1-methyl-butyl, 2-methyl-butyl, 3- methyl-butyl, 2,2-dimethyl-propyl, 1-ethyl-propyl, hexyl, 1,1-dimethyl-propyl, 1,2- dimethyl-propyl, 1-methyl-pentyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 1,1- dimethyl-butyl, 1,2-dimethyl-butyl, 1,3-dimethyl-butyl, 2,2-dimethyl-butyl, 2,3-dimethyl-butyl, 3,3-dimethyl-butyl, 1-ethyl-butyl, 2-ethyl-butyl, 1,1,2-trimethyl-propyl,
  • cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
  • the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.”
  • a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy”
  • a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like.
  • alkenyl refers to unsaturated, straight-chained, or branched hydrocarbon moieties containing a double bond.
  • C2- C 24 (e.g., C 2 -C 22 , C 2 -C 20 , C 2 -C 18 , C 2 -C 16 , C 2 -C 14 , C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 , C 2 -C 4 ) alkenyl groups are intended.
  • Alkenyl groups may contain more than one unsaturated bond.
  • Examples include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2- propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1- butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2- propenyl, 1-hexeny
  • substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiosulfonate (e.g., -SSO2Ra), or thiol, as described below, provided that the substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied.
  • substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, sily
  • alkynyl represents straight-chained or branched hydrocarbon moieties containing a triple bond.
  • C2-C24 e.g., C 2 -C 22 , C 2 -C 20 , C 2 -C 18 , C 2 -C 16 , C 2 -C 14 , C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 , C 2 -C 4
  • Alkynyl groups may contain more than one unsaturated bond.
  • heteroaryl is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group.
  • heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus.
  • non-heteroaryl which is included in the term “aryl,” defines a group that contains an aromatic group that does not contain a heteroatom.
  • the aryl or heteroaryl substituents may be unsubstituted or substituted with one or more chemical moieties.
  • heterocycloalkyl is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • cyclic group is used herein to refer to either aryl groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups), or both. Cyclic groups have one or more ring systems that can be substituted or unsubstituted. A cyclic group can contain one or more aryl groups, one or more non-aryl groups, or one or more aryl groups and one or more non-aryl groups. Attorney Docket No.103361-086WO1 As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen.
  • the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-10 ring atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six- membered heteroaryl ring.
  • a five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S.
  • Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3- triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4- thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.
  • a six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S.
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • heterocycloalkyl refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S.
  • heterocycloalkyl monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups.
  • Heterocycloalkyl groups can also include spirocycles.
  • Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like.
  • Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.).
  • the heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom.
  • the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.
  • heterocycloalkyl Also included in the definition of heterocycloalkyl are Attorney Docket No.103361-086WO1 moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • the heterocycloalkyl has 4-10, 4-7 or 4-6 ring atoms with 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.
  • the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin- 3-yl ring is attached at the 3-position.
  • acyl as used herein is represented by the formula –C(O)Z 1 where Z 1 can be a hydrogen, hydroxyl, alkoxy, alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • Z 1 can be a hydrogen, hydroxyl, alkoxy, alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • acyl can be used interchangeably with “carbonyl.”
  • alkoxy refers to a group of the formula Z 1 -O-, where Z 1 is unsubstituted or substituted alkyl as defined above. Unless otherwise specified, alkoxy groups wherein Z 1 is a C1-C24 (e.g., C1-C22, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C 1 -C 8 , C 1 -C 6 , C 1 -C 4 ) alkyl group are intended.
  • C1-C24 e.g., C1-C22, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C 1 -C 8 , C 1 -C 6 , C 1 -C 4
  • Examples include methoxy, ethoxy, propoxy, 1-methyl-ethoxy, butoxy, 1-methyl-propoxy, 2-methyl-propoxy, 1,1-dimethyl- ethoxy, pentoxy, 1-methyl-butyloxy, 2-methyl-butoxy, 3-methyl-butoxy, 2,2-di-methyl- propoxy, 1-ethyl-propoxy, hexoxy, 1,1-dimethyl-propoxy, 1,2-dimethyl-propoxy, 1- methyl-pentoxy, 2-methyl-pentoxy, 3-methyl-pentoxy, 4-methyl-penoxy, 1,1-dimethyl- butoxy, 1,2-dimethyl-butoxy, 1,3-dimethyl-butoxy, 2,2-dimethyl-butoxy, 2,3-dimethyl- butoxy, 3,3-dimethyl-butoxy, 1-ethyl-butoxy, 2-ethylbutoxy, 1,1,2-trimethyl-propoxy, 1,2,2-trimethyl-propoxy, 1-ethyl-1-methyl-propoxy, and 1-ethyl
  • aldehyde as used herein is represented by the formula —C(O)H.
  • amine or “amino” as used herein are represented by the formula — NZ 1 Z 2 , where Z 1 and Z 2 can each be substitution group as described herein, such as hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, Attorney Docket No.103361-086WO1 cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • “Amido” is —C(O)NZ 1 Z 2 .
  • carboxylic acid as used herein is represented by the formula — C(O)OH.
  • a “carboxylate” or “carboxyl” group as used herein is represented by the formula —C(O)O-.
  • esteer as used herein is represented by the formula —OC(O)Z 1 or —C(O)OZ 1 , where Z 1 can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • ether as used herein is represented by the formula Z 1 OZ 2 , where Z 1 and Z 2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • ketone as used herein is represented by the formula Z 1 C(O)Z 2 , where Z 1 and Z 2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • halide or “halogen” or “halo” as used herein refers to fluorine, chlorine, bromine, and iodine.
  • hydroxyl as used herein is represented by the formula —OH.
  • nitro as used herein is represented by the formula —NO 2 .
  • Me refers to a methyl group
  • OMe refers to a methoxy group
  • i-Pr refers to an isopropyl group.
  • R 1 ,” “R 2 ,” “R 3 ,” “R n ,” etc., where n is some integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an amine group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • the amino group can be incorporated within the backbone of the alkyl group.
  • the amino group can be attached to the backbone of the alkyl group.
  • the nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • substituted refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents.” The molecule can be multiply substituted.
  • the ring when R 10 and R 9 together form an optionally substituted ring, the ring may be referred to as ring G.
  • the compound may be of the formula: Formula Ia or a pharmaceutically acceptable salt thereof, wherein ring G is an optionally substituted monocyclic or bicyclic heteroaryl ring and wherein n, m, E, D, Y 2 to Y 4 , and R 1’ -R 8’ and R 11’ are as described above for Formula I.
  • nitrogen containing heteroaryl rings include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl, furazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, 4H-quinolizinyl, quinolinyl, Attorney Docket No.103361-086WO1 isoquinolinyl, cinnolinyl, phthalazinyl, quin
  • the small molecule USP30 inhibitor can be defined by the formula: Formula Ia-1 or a pharmaceutically acceptable salt thereof; wherein G, Y 1 , Y 3 , Y 4 , and R 11’ are as described above for Formula Ia; R 1’ to R 2’ and R 5’ to R 8’ , each independently represent a hydrogen, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, ether, and amine, an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl, or an optionally substituted 5 to 10 membered heteroaryl or aryl; one or more spirocyclic groups where R 1’ is linked to R 2’ , R 5’ is linked to R 6’ , or R 8
  • the small molecule USP30 inhibitor can be defined by the formula: or a pharmaceutically acceptable salt thereof; wherein Y 1 , Y 3 , Y 4 , R 9 , R 10 , and R 11’ are as described above for Formula I; R 1’ to R 2’ and R 5’ to R 8’ , each independently represent a hydrogen, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, ether, and amine, an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl, or an optionally substituted 5 to 10 membered heteroaryl or aryl; one or more spirocyclic groups where R 1’ is linked to R 2’ , R 5’ is linked to R 6’ , or R
  • the small molecule USP30 inhibitor can be defined by the formula: a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein: A is an aryl; R 1 is selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, ether, and amine; R 3 , R 4 and R 5 are each independently selected from hydrogen, deuterium, and halogen; and Attorney Docket No.103361-086WO1 R 6 is selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkoxy and cycloalkoxy.
  • A is selected from: wherein: R 2 is selected from hydrogen and alkyl; X, Y, and Z are each independently N, O, or C; wherein either: (i) X 1 is CH; one of X 2 and X 3 is CR 7 , and the other is N; or (ii) X 1 is CH or N; X 2 is N; and X 3 is CR 8 or N; and R 7 and R 8 are each independently selected from hydrogen, halogen, (C1- C 3 )alkyl and (C 1 -C 3 )alkoxy.
  • the small molecule USP30 inhibitor can be defined by the formula: Formula IIb wherein: R 1 is selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, ether, and amine; R 3 , R 4 and R 5 are each independently selected from hydrogen, deuterium, and halogen; and Attorney Docket No.103361-086WO1 R 6 is selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkoxy and cycloalkoxy. R 2 is selected from hydrogen and alkyl; X is N, O, or C. In some embodiments, X is C.
  • X is C
  • R 1 is selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )fluoroalkyl, CH 2 OCH 3 and CH 2 N(CH 3 ) 2
  • R 2 is selected from hydrogen and methyl
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium and fluorine.
  • X is N.
  • X is N
  • R 1 is selected from (C1-C4)alkyl, (C1-C4)fluoroalkyl and CH2OCH3
  • R3, R4 and R5 are each independently selected from hydrogen and fluorine
  • R 6 is selected from hydrogen, fluorine, (C1- C 4 )alkoxy and cyclopropoxy.
  • the small molecule USP30 inhibitor can be defined by the formula: wherein: R 1 is selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, ether, and amine; R 3 , R 4 and R 5 are each independently selected from hydrogen, deuterium, and halogen; and R 6 is selected from hydrogen, halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy and cycloalkoxy.
  • R 7 and R 8 are each independently selected from hydrogen, halogen, (C1- C3)alkyl and (C1-C3)alkoxy.
  • R 1 is selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and CH 2 OCH 3 .
  • R 3 , R 4 and R 5 are each independently selected from hydrogen and deuterium.
  • the optionally substituted 5 to 10 membered nitrogen-containing monocyclic or bicyclic heterocyclyl or heteroaryl ring may be selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, purinyl, furazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl,
  • the small molecule USP30 inhibitor can be defined by the formula: Formula IIIb wherein R 1’ , R 2’ , R 5’ , R 6’ , Y 1 , and Y 3 are as described above for Formula I; Attorney Docket No.103361-086WO1 wherein X 1a , X 1b , X 1c , and X 1d can be each independently N, CH, or one or more - Q 1 -(R a )n, wherein each occurrence of-Q 1 (R a )n is the same or different, wherein; n is 0 or 1; Q 1 represents halogen, cyano, oxo, nitro, -OR 5a , -SR 5a , -NR 5a R 6a , - CONR 5a R 6a , -NR 5a COR 6a , -NR 5a CONR 6a R 7a , - COR 5a , -C(O)OR 5a
  • the small molecule USP30 inhibitor can be defined by the formula: Formula IV or a pharmaceutically acceptable salt thereof; wherein: E is O, N(R c ), and -C(R 13 )(R 14 )-; R 13 and R 14 each independently represent hydrogen, halogen, cyano, hydroxyl, an optionally substituted C 1 -C 3 alkyl or an optionally substituted C 1 -C 3 alkoxy group, a 3 to 6 membered heterocyclyl, heteroaryl, cycloalkyl or aryl ring, and a spirocyclic group where R 13 is linked to R 13 or R 14 is linked to R 8’ or R 11’ to form an optionally substituted C 3 -C 4 cycloalkyl; R c is selected from hydrogen, optionally substituted C 1 -C 3 alkyl, C(O)R ' , S(O) 2 R ' , and a 3 to 6 membered heterocyclyl, heteroaryl,
  • the optionally substituted 5 to 10 membered nitrogen-containing monocyclic or bicyclic heterocyclyl or heteroaryl ring may be selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, purinyl, furazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quina
  • the small molecule USP30 inhibitors as described herein may be administered in combination with other therapies such as, for example, radiation therapy, surgery, conventional chemotherapy, or with a combination of one or more additional therapies.
  • the methods and small molecule USP30 inhibitors derived from this invention may be administered alone in a pharmaceutical composition or combined with therapeutically effective and physiologically acceptable amount of one or more other active ingredients or agents.
  • Such other active ingredient includes, but is not limited to chemotherapeutic agent(s).
  • the small molecule USP30 inhibitors described in herein may be administered in combination with other therapies simultaneously or sequentially. The separation in time between administrations may be minutes, hours, days or it may be longer.
  • glutathione antagonists include but are not limited to buthionine sulfoximine, F ⁇ FORSKRVSKDPLGH ⁇ LIRVSKDPLGH ⁇ DFWLQRP ⁇ FLQ ⁇ G ⁇ DQG ⁇ 1 ⁇ K ⁇ GUR[ ⁇ SKHQ ⁇ O ⁇ UHWLQDPLGH ⁇ HPR).
  • chemotherapeutic agents that can be combined with the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy described herein include: synthetic, semisynthetic and naturally derived agents.
  • Illustrative immune checkpoint targets for blocking or inhibition include, but are not limited to, &7/$ ⁇ 3'/ ⁇ 3'/ ⁇ 3' ⁇ % ⁇ + ⁇ % ⁇ + ⁇ %7/$ ⁇ +9(0 ⁇ *$/ ⁇ /$* ⁇ 7,0 ⁇ 9,67$ ⁇ .,5 ⁇ % ⁇ EHORQJV ⁇ WR ⁇ WKH CD2 family of molecules and is expressed on all NK, ⁇ and memory CD8+ ( ⁇ T cells), CD160 (also UHIHUUHG ⁇ WR ⁇ DV ⁇ % ⁇ &*(1 ⁇ &+. ⁇ DQG ⁇ &+. ⁇ NLQDVHV ⁇ $ ⁇ D5 ⁇ DQG ⁇ YDULRXV ⁇ % ⁇ IDPLO ⁇ OLJDQGV ⁇ % ⁇ IDPLO ⁇ OLJDQGV ⁇ LQFOXGH ⁇ EXW ⁇ DUH ⁇ QRW ⁇ OLPLWHG ⁇ WR ⁇ % ⁇ % ⁇ % ⁇ '& ⁇ % ⁇ + ⁇ % ⁇ + ⁇ % ⁇ + ⁇ % ⁇ + ⁇ DQ
  • the USP30 inhibitors as used in the methods described herein can be administered by any suitable method and technique presently or prospectively known to those skilled in the art.
  • the active components described herein can be formulated in a physiologically- or pharmaceutically-acceptable form and administered by any suitable route known in the art including, for example, oral and parenteral routes of administering.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection.
  • Administration of the active components of their compositions can be a single administration, or at continuous and distinct intervals as can be readily determined by a person skilled in the art.
  • compositions comprising an active compound and an excipient of some sort may be useful in a variety of medical and non-medical applications.
  • excipients include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • General considerations in formulation and/or manufacture can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.
  • cross-linked poly(vinyl-pyrrolidone) crospovidone
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays Attorney Docket No.103361-086WO1 (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g.
  • natural emulsifiers e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
  • colloidal clays Attorney Docket No.103361-086WO1
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol
  • carbomers e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer
  • carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • Cremophor polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl- pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, Attorney Docket No.103361-086WO1 potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
  • the preservative is an anti-oxidant.
  • the preservative is a chelating agent.
  • buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium Attorney Docket No.103361-086WO1 phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buck
  • Exemplary polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethyl cellulose (CMC) and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts, carboxymethylhydroxyethylcellulose (CMHEC) and its various salts, other polysaccharides and polysaccharide derivatives such as starch, dextran, dextran Attorney Docket No.103361-086WO1 derivatives, chitosan, and alginic acid and its various salts, carageenan, various gums, including xanthan gum, guar gum, gum
  • composition may further comprise an emulsifying agent.
  • emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N-vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non- cationic polyacrylates, such as poly (meth) acrylic acid, and esters amide and hydroxy alkyl amides thereof, natural emulsifiers (e.g.
  • polyoxyethylene sorbitan monolaurate [Tween 20] polyoxyethylene Attorney Docket No.103361-086WO1 sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g.
  • polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g.
  • polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • the emulsifying agent is cholesterol.
  • Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid composition may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable compositions for example, injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be an injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer's solution, U.S.P.
  • the injectable composition can be sterilized, for Attorney Docket No.103361-086WO1 example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.
  • Solid compositions include capsules, tablets, pills, powders, and granules.
  • the particles are mixed with at least one excipient and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate,
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • Tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • the ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art.
  • the dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms or disorder are affected.
  • the dosage should not be so large as to cause adverse side effects, such as unwanted cross- reactions, anaphylactic reactions, and the like.
  • the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art.
  • the dosage can be adjusted by the individual physician in the event of any counterindications.
  • Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.
  • the composition as used in the methods described herein may be administered in combination or alternation with one or more additional active agents.
  • additional active agents include anti-inflammatory Attorney Docket No.103361-086WO1 agents (including steroids and non-steroidal anti-inflammatory agents), anti-coagulant agents, antiplatelet agents, and antiseptic agents.
  • steroidal anti-inflammatory agents include, but are not limited to, hydrocortisone, dexamethasone, prednisolone, prednisone, triamcinolone, methylprednisolone, budesonide, betamethasone, cortisone, and deflazacort.
  • Mitophagy is the regulated process that targets damaged or dysfunctional mitochondria for lysosomal-mediated removal. This process is an essential element of mitochondrial quality control, and dysregulation of mitophagy may contribute to a host of diseases, most notably neurodegenerative conditions such as Parkinson’s disease. Mitochondria targeted for mitophagic destruction are molecularly marked by the Attorney Docket No.103361-086WO1 ubiquitination of several outer mitochondrial membrane (OMM) proteins.
  • OMM outer mitochondrial membrane
  • Mitophagy declines with age and, dysregulation of mitophagy is associated with a wide range of age-related human diseases, most notably neurodegenerative conditions such as Parkinson’s disease (PD).
  • PD neurodegenerative conditions
  • the understanding of the mechanisms that govern mitophagy and regulate the removal of mitochondria upon mitochondrial damage has advanced vastly.
  • OMM outer mitochondrial membrane proteins
  • the E3-ubiquitin ligase, Parkin has been implicated as a critical enzyme that catalyzes the ubiquitination of a wide range of mitochondrial proteins.
  • Parkin s recruitment to the mitochondria involves the PTEN-induced putative kinase 1 (PINK1), a mitochondrial-targeted kinase whose Attorney Docket No.103361-086WO1 stability is regulated, at least in part, by mitochondrial membrane potential, suggesting that PINK1 and Parkin function in the same biochemical pathway.
  • Loss-of-function mutations in PINK1 or Parkin also have been identified as a cause for familial, early-onset Parkinson disease, strengthening the premise that these two proteins are critical for optimal mitochondrial quality control.
  • the use of innovative mouse models and patient-derived induced pluripotent stem cells (iPSCs) has dramatically enhanced our ability to further explore the clinical relevance of mitophagy and create therapies where mitophagy modulation may prove beneficial.
  • USP30 In addition, genetic manipulations of USP30 have begun to elucidate how this enzyme contributes to the process of mitophagy. In cultured cells, including neurons, USP30 overexpression inhibits mitophagy, and this effect is not seen when a catalytically inactive mutant of USP30 is employed. Furthermore, the knockdown of USP30 enhances mitophagy in cultured cells. Interestingly, knockdown of USP30 can rescue the defect in mitophagy seen in Parkin or PINK1-deficient flies. These, and subsequent observations, have suggested that inhibiting USP30 might provide a specific strategy to increase mitophagic flux selectively.
  • cells stably expressing mt-Keima were incubated in medium containing a mixture of 1 ⁇ M oligomycin and 1 ⁇ M antimycin A for 1.5 h. Prior to A/O treatment, cultures were treated with DMSO or ST-539 at 3 ⁇ g/ml. Cells were trypsinized, washed once with PBS buffer and then resXVSHQGHG ⁇ LQWR ⁇ O ⁇ RI ⁇ 3%6 ⁇ SULRU ⁇ WR ⁇ DQDO ⁇ VLV ⁇ using a BD Fortessa flow cytometer as previously described.
  • the membranes were incubated with anti-rabbit (LI-COR, 926-32211, Attorney Docket No.103361-086WO1 1:15000) or anti-mouse (LI-COR, 926-68072, 1:15000) IgG secondary antibodies for 1 h at room temperature. Images were captured using the Odyssey system (LI-Cor). One representative blot is shown of three independent experiments. Seahorse assay Measurement of intact cellular respiration was performed using the Seahorse XFe96 Analyzer as previously described.
  • fluorescence of mt-Keima was imaged in two channels via two sequential excitations (458 nm, green; 561 nm, red) and using a 570- to 695-nm emission range.
  • Confocal experiments for parkin translocation were performed using a HeLa cell line stably expressing YFP-Parkin plated on 35mm coverglass #1.5 chamber dishes (MatTek). These cells were treated for 2 h with DMSO as vehicle control or with A/O.
  • YFP was imaged with a 514-nm excitation and 520- to 570- emission filters. Representative confocal images were processed using Imaris software by contrast linear stretch only.
  • mice were lightly anesthetized with isoflurane and the ejection fraction, fractional shortening, and ventricular chamber dimensions were determined using 2-D-guided M mode images. Ejection fraction, fractional shortening, ventricular chamber dimensions, and left ventricular mass were calculated automatically using the VevoLAB program. All experiments involving animals were approved by the Institutional Animal Care and Use Committee at The Ohio State University. Pharmacokinetics ST-539 was dissolved into 1% DMSO in Sesame oil and injected intraperitoneally (i.p.) at doses of 25 mg/kg. Serial blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4 and 8 hours post dosing. Mice were euthanized at 24 hours post dosing.
  • a terminal blood sample was collected by cardiac puncture followed by harvesting the brain and heart. Transcardial perfusion was performed prior to brain collection.
  • the blood samples were placed in microtubes pretreated with K 2 EDTA as an anticoagulant and kept on ice until centrifugation.
  • the tissue samples were rinsed using cold distilled water to remove blood, blotted dry, weighed and stored on dry ice until LC/MS/MS analysis.
  • Plasma was transferred into polypropylene tubes or 96-well plates, quick frozen on dry ice, and stored at - 70 ⁇ 10°C until LC/MS/MS analysis.
  • Results ST-539 inhibits USP30 and promotes mitophagy
  • the enzymatic activity of Parkin is to function as an E3 ubiquitin ligase.
  • Evidence suggests that Parkin can ubiquitinate a wide range of OMM proteins, including the translocase of outer membrane 20 (TOM20).
  • TOM20 translocase of outer membrane 20
  • Hasson SA Kane LA, Yamano K, et al. High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature. 2013;504(7479):291-295.
  • Sarraf SA Raman M, Guarani-Pereira V, et al. Landscape of the PARKIN- dependent ubiquitylome in response to mitochondrial depolarization. Nature. 2013;496(7445):372-376.

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Abstract

Disclosed herein are small molecule inhibitors of USP30 and their use in treating, ameliorating and/or preventing cardiomyopathy. Additionally, disclosed herein are methods of inhibiting the USP30 pathway and activity comprising contacting a cell expressing USP30 or administering to a subject in need of USP30 inhibition, any of the small molecule USP30 inhibitors disclosed herein. Also disclosed are chemotherapeutic regimens for the treatment of cancer that include a small molecule USP30 inhibitor in combination with chemotherapeutic agent to treat the cancer, as well as methods of treating cancer using these regimens.

Description

Attorney Docket No.103361-086WO1 COMPOSITIONS AND METHODS FOR PREVENTING CARDIOMYOPATHY CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of priority of U.S. Provisional Application No. 63/417,609, filed October 19, 2022, which is incorporated herein by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant no. K22 HL135051 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Cardiomyopathy refers to diseases of the heart muscle. These diseases have many causes, signs and symptoms, and treatments. In cardiomyopathy, the heart muscle becomes enlarged, thick, or rigid. In rare cases, the muscle tissue in the heart is replaced with scar tissue. As cardiomyopathy worsens, the heart becomes weaker. It is less able to pump blood through the body and maintain a normal electrical rhythm. This can lead to heart failure or irregular heartbeats called arrhythmias. In turn, heart failure can cause fluid to build up in the lungs, ankles, feet, legs, or abdomen. The weakening of the heart also can cause other complications, such as heart valve problems. The main types of cardiomyopathy are dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular dysplasia. Other types of cardiomyopathy sometimes are referred to as “unclassified cardiomyopathy.” Cardiomyopathy can be acquired or inherited, with hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia substantially being inherited disorders. However, in many cases, cardiomyopathy can be induced by other diseases or conditions, or by various toxins or drugs. For example, dilated cardiomyopathy can result from coronary heart disease, heart attack, high blood pressure, diabetes, thyroid disease, viral hepatitis, and HIV; infections, especially viral infections that inflame the heart muscle can result in cardiomyopathy; alcohol, especially in conjunction with a poor diet; complications during the last month of pregnancy or within 5 months of birth; certain Attorney Docket No.103361-086WO1 toxins, such as cobalt; and certain drugs (such as cocaine and amphetamines) and chemotherapeutic drugs (e.g., anthracyclines such as doxorubicin and daunorubicin) and drugs for the treatment of diabetes, which can result in abrupt cardiomyopathic events. Restrictive cardiomyopathy can result from conditions such as hemochromatosis, sarcoidosis, amyloidosis, and connective tissue disorders, as well as some cancer treatments, such as radiation and chemotherapy. These events pose a significant public health concern. Accordingly, there is a significant need for compositions and methods for mitigating cardiomyopathy, particularly drug-induced cardiomyopathy. SUMMARY Provided herein are small molecule inhibitors of USP30 and methods of using thereof. For example, provided herein are methods of treating, ameliorating and/or preventing cardiomyopathy in a subject in need thereof that comprise administering to the subject an effective amount of a small molecule USP30 inhibitor to inhibit, decrease, or reduce USP30 activity. The cardiomyopathy can have a variety of etiologies. In some embodiments, the cardiomyopathy can be drug induced cardiomyopathy. For example, the cardiomyopathy can be caused or induced by a drug such as an anthraquinone, an antipsychotic phenothiazine derivate, an arnica herb, arsenic, an amphetamine, an anabolic-androgenic steroids, an azidothymidine, an anagrelide, a catecholamines, cytarabine, clozapine, cobalt, cocaine, chloroquine, a cyclophosphamide, a diazoxide, an anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), ethanol, imatinib, isoproterenol, ephedrine, melarsoprol, methamphetamine, methylphenidate, minoxidil, mitomycin, mitoxantrone, paclitaxel, pentamidine, stibogluconate, sunitinib, trastuzumab, tricyclic antidepressants, zidovudine, or a combination thereof. In certain embodiments, the cardiomyopathy can be caused or induced by an anthracycline. In certain embodiments, the cardiomyopathy can be caused or induced by doxorubicin. In some embodiments, the method can further comprise administering the small molecule USP30 inhibitor in combination with other therapies such as, radiation therapy, surgery, conventional chemotherapy, or with a combination of one or more additional therapies. In certain embodiments, the conventional chemotherapy comprises a Attorney Docket No.103361-086WO1 chemotherapeutic agent inducing cardiomyopathy. The chemotherapeutic agent inducing cardiomyopathy can comprise, for example, an anthracycline (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone). In some embodiments, the cardiomyopathy can be caused or induced by a viral infection, coronary artery disease, or high blood pressure. For example, in some embodiments, the cardiomyopathy can be caused or induced by viral infection caused by a virus selected from Coxsackie B and adenovirus, echoviruses, influenza H1N1, Epstein- Barr virus, rubella virus, varicella-zoster virus, mumps virus, measles virus, paroviruses, yellow fever virus, dengue virus, polio virus, rabies virus and the viruses that cause hepatitis A virus and hepatitis C virus, and coronaviruses such as SARS-COV-2. In certain embodiments, the cardiomyopathy can be caused or induced by a SARS-COV-2 infection (e.g., Covid-19). The USP30 inhibitor can be administered by any suitable route. For example, in some embodiments, the USP30 inhibitor can be administered orally, topically, intravenously, subcutaneously, transcutaneous, transdermally, intramuscularly, intradermally, intraventricularly, intracranially, or intraperitoneally. Also provided are methods of treating cancer in a subject in need thereof that comprise administering to the subject a chemotherapeutic agent and an effective amount of a small molecule USP30 inhibitor to inhibit, decrease, or reduce USP30 activity. In some embodiments, the chemotherapeutic agent can comprise an anthracycline (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and/or mitoxantrone). Also provided are chemotherapeutic regimens for the treatment of cancer. These regimens can comprise a therapeutically effective amount of a chemotherapeutic agent to treat the cancer and an effective amount of a small molecule USP30 inhibitor to inhibit, decrease, or reduce USP30 activity. In some embodiments, the chemotherapeutic agent can comprise an anthracycline (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and/or mitoxantrone). The details of one or more embodiments of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims. Attorney Docket No.103361-086WO1 DESCRIPTION OF DRAWINGS Figures 1A-1D illustrate that a USP30 inhibitor, St-539, promotes mitophagy. Figure 1A shows the analysis of TOM20 ubiquitination, as well as levels of TOM20, TIM23, and TOM40 in the presence or absence of A/O treatment in HeLa cells expressing Parkin or Parkin/Myc-tagged USP30. Shown is one representative western blot from three independent experiments, all providing similar results. Figure 1B shows the chemical structure of ST-539. Figure 1C shows representative immunoblotting for TOM20 TOM40 and TIM23 in HeLa cells expressing Parkin or Parkin/Myc-tagged USP30. Prior to A/O treatment, cultures were treated with ST-539 at indicated concentrations. Figure 1D shows representative FACS analysis of AO-induced mitophagy using mt-Keima fluorescence. Cells were treated with A/O for 2h and analyzed by FACS for lysosomal positive mt- Keima (pH4). Prior to A/O treatment, cultures were treated with DMSO or ST- 539(3μg/ml). Figures 2A-2C show that the inhibition of USP30 by ST-539 requires PINK1 and Parkin. Figure 2A shows representative confocal images of wild type (WT) and PINK1 KO cells expressing YFP-Parkin and mt-Keima following 2h DMSO (C) or A/O treatment. The mt-Keima emission signal obtained after excitation with the 458-nm laser is shown in green, and that obtained after excitation with the 561-nm laser is shown in red. After treatment with A/O, recruitment of Parkin to the mitochondria (shown in cyan) and an increase in mitophagy (shown in red) can be observed in WT HeLa cells but not in PINK1 KO cells. Scale bar: 20 μm. Figure 2B shows the analysis of TOM20 ubiquitination in HeLa cells, HeLa cells expressing YFP-Parkin and PINK1 KO Hela cells expressing YFP-Parkin. Prior to A/O treatment, cultures were treated with ST-539 at 1 or ^^g/ml. Figure 2C shows representative immunoblotting for TOM20 and NDP52 in HeLa cells, HeLa cells expressing YFP-Parkin and PINK1 KO HeLa cells expressing YFP- Parkin or Parkin/Myc-tagged USP30 following A/O treatment for 18h. Prior to A/O treatment, cultures were treated with 3^g/ml ST-539. Figures 3A-3D show that ST-539 has minimal effect on mitochondrial function in cells. Figure 3A is a bar graph showing the quantification of TMRM signal in Hela-Parkin or HeLa-Parkin/USP30 cells in the presence or absence of ST-539 (ST, 3 or 10^g/ml) or FCCP (10^M). The intensity of TMRM reflects the level of mitochondrial membrane potential (ǻȌm). Values are normalized to the vehicle (DMSO) treated samples. Data represent mean ± SD of three independent experiments. Figure 3B shows HeLa-Parkin Attorney Docket No.103361-086WO1 (upper) or HeLa-Parkin/USP30 (lower) cells analyzed using a Seahorse XF96 analyzer. Slightly increased basal respiration and spare respiratory capacity were observed in both cells after ST-539 treatment. A total of three different pair of MEFS were analyzed, all giving similar results. Figure 3C shows representative confocal images of WT and Mfn2í^í MEF cells untreated or treated with 10^g/ml ST-539 for 24 h. Scale bar, 20 ^m. Cells were stained with Mito Tracker Red ™ for visualization of mitochondria. Figure 3D shows the quantification of the indicated cells with connected and tubular mitochondria before and after 3 or 10^g/ml ST-539 treatment for 24 h. Data represent mean ± SD of three independent experiments, each with > 100 cells counted per condition. Figures 4A-4C show USP30 inhibition promotes cardiac mitophagy. Figure 4A shows plasma ST-539 concentrations as a function of time following 25mg/kg i.p. injection into adult male mice. Concentration determined by LC-MS/MS. n=3 males/time point. Data presented as mean ± s.d. Figure 4B provides an assessment of mitophagy using mt-Keima mice. Left, representative confocal images of heart and liver tissue from vehicle or ST-539 (25mg/kg/day for 5 days) treated mt-Keima mice; right, quantification of cardiac and hepatic mitophagy. The emission signal obtained after excitation with the 458-nm laser is shown in green, and that obtained after excitation with the 561-nm laser is shown in red. Individual mouse data points are shown. Values are normalized to control levels of mitophagy (n=4 for control and n=5 for ST-^^^^^^6FDOH^EDUV^^^^ௗ^m. † pௗ^ௗ^^^^^^Figure 4C details echocardiographic quantification showing similar percentage ejection fraction (EF) cardiac output and left ventricular posterior wall thickness at end-systole (LVPWs) for vehicle or ST-539 treated mt-Keima mice (n=4 for control and n=5 for ST-539). Data are PHDQௗ^ௗV^G^^,QGLYLGXDO^PRXVH^GDWD^SRLQWV^DUH^VKRZQ^ Figure 5 shows representative immunoblotting for expression of PINK1 in Hela WT cells or PINK1 KO cells expressing Parkin. ACTIN is shown as a loading control. Figures 6A and 6B show representative immunoblotting for (Figure 6A) TOM20 and TIM23 or (Figure 6B) TOM40 and LC3 in Hela cells expressing Parkin or Parkin/Myc- tagged USP30 following A/O treatment for 18h. Prior to A/O treatment, cultures were treated with ST-539 at indicated concentrations Figures 7A-7B show representative immunoblotting for LC3 I/II of heart (Figure 7A) and liver (Figure 7B) tissue from vehicle or ST-539 (25mg/kg/day for 5 days) treated mice. ST-539 treated hearts exhibited increased levels of LC3-II compared to vehicle treated Attorney Docket No.103361-086WO1 hearts, consistent with augmented cardiac mitophagy following ST-539 treatment. Data are PHDQௗ^ௗV^G^^^Sௗ^ௗ^^^^^ Figures 8A-8D further illustrate that USP30 inhibition promotes cardiac mitophagy. Figure 9 shows that ST-539 reduces doxorubicin-induced cell death in Human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs). The plot in Figure 9 shows the percent survival of hiPSC-CMs 48 hours after treatment with vehicle (DMSO), doxorubicin, and doxorubicin+ST-539. Figure 10 shows that ST-539 potentiates doxorubicin-induced apoptosis in leukemia. The plot in Figure 10 shows the percent cell viability of Jurkat T cells 48 hours after treatment with ST-539 and doxorubicin, as determined using a Resazurin assay. DETAILED DESCRIPTION A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. Definitions To facilitate understanding of the disclosure set forth herein, a number of terms are defined below. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference. General Definitions The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments of the invention and are also disclosed. Other than where noted, all numbers expressing quantities of ingredients, reaction conditions, geometries, dimensions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches. Attorney Docket No.103361-086WO1 As used in this specification and the following claims, the terms “comprise” (as well as forms, derivatives, or variations thereof, such as “comprising” and “comprises”) and “include” (as well as forms, derivatives, or variations thereof, such as “including” and “includes”) are inclusive (i.e., open-ended) and do not exclude additional elements or steps. For example, the terms "comprise" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. Accordingly, these terms are intended to not only cover the recited element(s) or step(s), but may also include other elements or steps not expressly recited. Furthermore, as used herein, the use of the terms “a”, “an”, and “the” when used in conjunction with an element may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” Therefore, an element preceded by “a” or “an” does not, without more constraints, preclude the existence of additional identical elements. The use of the term “about” applies to all numeric values, whether or not explicitly indicated. This term generally refers to a range of numbers that one of ordinary skill in the art would consider as a reasonable amount of deviation to the recited numeric values (i.e., having the equivalent function or result). For example, this term can be construed as including a deviation of ±10 percent of the given numeric value provided such a deviation does not alter the end function or result of the value. Therefore, a value of about 1% can be construed to be a range from 0.9% to 1.1%. Furthermore, a range may be construed to include the start and the end of the range. For example, a range of 10% to 20% (i.e., range of 10%-20%) can includes 10% and also includes 20%, and includes percentages in between 10% and 20%, unless explicitly stated otherwise herein. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. By “about” is meant within 5% of the value, e.g., within 4, 3, 2, or 1% of the value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and Attorney Docket No.103361-086WO1 independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. As used herein, the terms "may," "optionally," and "may optionally" are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur. Thus, for example, the statement that a formulation "may include an excipient" is meant to include cases in which the formulation includes an excipient as well as cases in which the formulation does not include an excipient. Administration" to a subject includes any route of introducing or delivering to a subject an agent. Administration can be carried out by any suitable route, including oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation, via an implanted reservoir, parenteral (e.g., subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injections or infusion techniques), and the like. "Concurrent administration", "administration in combination", "simultaneous administration" or "administered simultaneously" as used herein, means that the compounds are administered at the same point in time or essentially immediately following one another. In the latter case, the two compounds are administered at times sufficiently close that the results observed are indistinguishable from those achieved when the compounds are administered at the same point in time. "Systemic administration" refers to the introducing or delivering to a subject an agent via a route which introduces or delivers the agent to extensive areas of the subject's body (e.g. greater than 50% of the body), for example through entrance into the circulatory or lymph systems. By contrast, "local administration" refers to the introducing or delivery to a subject an agent via a route which introduces or delivers the agent to the area or area immediately adjacent to the point of administration and does not introduce the agent systemically in a therapeutically significant amount. For example, locally administered agents are easily detectable in the local vicinity of the point of administration but are undetectable or detectable at negligible amounts in distal parts of the subject's body. Administration includes self-administration and the administration by another. Attorney Docket No.103361-086WO1 As used here, the terms “beneficial agent” and “active agent” are used interchangeably herein to refer to a chemical compound or composition that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, i.e., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, i.e., prevention of a disorder or other undesirable physiological condition. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, isomers, fragments, analogs, and the like. When the terms “beneficial agent” or “active agent” are used, then, or when a particular agent is specifically identified, it is to be understood that the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, conjugates, active metabolites, isomers, fragments, analogs, etc. A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant. "Inhibit," "inhibiting," and "inhibition" mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels. “Inactivate”, “inactivating” and “inactivation” means to decrease or eliminate an activity, response, condition, disease, or other biological parameter due to a chemical (covalent bond formation) between the ligand and a its biological target. By “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g., tumor growth). It is understood that this Attorney Docket No.103361-086WO1 is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control. As used herein, the terms “treating” or “treatment” of a subject includes the administration of a drug to a subject with the purpose of preventing, curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, stabilizing or affecting a disease or disorder, or a symptom of a disease or disorder. The terms “treating” and “treatment” can also refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage. In particular, the term “treatment” includes the alleviation, in part or in whole, of the symptoms of coronavirus infection (e.g., sore throat, blocked and/or runny nose, cough and/or elevated temperature associated with a common cold). Such treatment may include eradication, or slowing of population growth, of a microbial agent associated with inflammation. By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. For example, the terms “prevent” or “suppress” can refer to a treatment that forestalls or slows the onset of a disease or condition or reduced the severity of the disease or condition. Thus, if a treatment can treat a disease in a subject having symptoms of the disease, it can also prevent or suppress that disease in a subject who has yet to suffer some or all of the symptoms. As used herein, the term “preventing” a disorder or unwanted physiological event in a subject refers specifically to the prevention of the occurrence of symptoms and/or their underlying cause, wherein the subject may or may not exhibit heightened susceptibility to the disorder or event. In particular embodiments, Attorney Docket No.103361-086WO1 “prevention” includes reduction in risk of coronavirus infection in patients. However, it will be appreciated that such prevention may not be absolute, i.e., it may not prevent all such patients developing a coronavirus infection, or may only partially prevent an infection in a single individual. As such, the terms “prevention” and “prophylaxis” may be used interchangeably. By the term “effective amount” of a therapeutic agent is meant a nontoxic but sufficient amount of a beneficial agent to provide the desired effect. The amount of beneficial agent that is “effective” will vary from subject to subject, depending on the age and general condition of the subject, the particular beneficial agent or agents, and the like. Thus, it is not always possible to specify an exact “effective amount”. However, an appropriate “effective’ amount in any subject case may be determined by one of ordinary skill in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an “effective amount” of a beneficial can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts. An “effective amount” of a drug necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. As used herein, a “therapeutically effective amount” of a therapeutic agent refers to an amount that is effective to achieve a desired therapeutic result, and a “prophylactically effective amount” of a therapeutic agent refers to an amount that is effective to prevent an unwanted physiological condition. Therapeutically effective and prophylactically effective amounts of a given therapeutic agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the subject. The term “therapeutically effective amount” can also refer to an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent (e.g., amount over time), effective to facilitate a desired therapeutic effect. The precise desired therapeutic effect will vary according to the condition to be treated, the tolerance of the subject, the drug and/or drug formulation to be administered (e.g., the potency of the therapeutic agent (drug), the concentration of drug in the formulation, and the like), and a variety of other factors that are appreciated by those of ordinary skill in the art. Attorney Docket No.103361-086WO1 As used herein, the term “pharmaceutically acceptable” component can refer to a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation of the invention and administered to a subject as described herein without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained. When the term “pharmaceutically acceptable” is used to refer to an excipient, it is generally implied that the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration. "Pharmaceutically acceptable carrier" (sometimes referred to as a "carrier") means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and/or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil/water or water/oil emulsion) and/or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as described further herein. As used herein, “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of Attorney Docket No.103361-086WO1 acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). Also, as used herein, the term “pharmacologically active” (or simply “active”), as in a “pharmacologically active” derivative or analog, can refer to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree. A “control” is an alternative subject or sample used in an experiment for comparison purposes. A control can be "positive" or "negative." As used herein, by a “subject” is meant an individual. Thus, the “subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.), and birds. “Subject” can also include a mammal, such as a primate or a human. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician. Administration of the therapeutic agents can be carried out at dosages and for periods of time effective for treatment of a subject. In some embodiments, the subject is a human. Chemical Definitions Terms used herein will have their customary meaning in the art unless specified otherwise. The organic moieties mentioned when defining variable positions within the general formulae described herein (e.g., the term “halogen”) are collective terms for the individual substituents encompassed by the organic moiety. Ph refers to a phenyl group. Attorney Docket No.103361-086WO1 The prefix Cn-Cm preceding a group or moiety indicates, in each case, the possible number of carbon atoms in the group or moiety that follows. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms present in a compound or moiety, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valency of the heteroatom. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound (e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. The term "optionally substituted," as used herein, means that substitution with an additional group is optional and therefore it is possible for the designated atom to be unsubstituted. Thus, by use of the term “optionally substituted” the disclosure includes examples where the group is substituted and examples where it is not. “Z1,” “Z2,” “Z3,” and “Z4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents. As used herein, the term “alkyl” refers to saturated, straight-chained or branched saturated hydrocarbon moieties. Unless otherwise specified, C1-C24 (e.g., C1-C22, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, or C1-C4) alkyl groups are intended. Examples of alkyl groups include methyl, ethyl, propyl, 1-methyl-ethyl, butyl, 1-methyl- propyl, 2-methyl-propyl, 1,1-dimethyl-ethyl, pentyl, 1-methyl-butyl, 2-methyl-butyl, 3- methyl-butyl, 2,2-dimethyl-propyl, 1-ethyl-propyl, hexyl, 1,1-dimethyl-propyl, 1,2- dimethyl-propyl, 1-methyl-pentyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 1,1- dimethyl-butyl, 1,2-dimethyl-butyl, 1,3-dimethyl-butyl, 2,2-dimethyl-butyl, 2,3-dimethyl- butyl, 3,3-dimethyl-butyl, 1-ethyl-butyl, 2-ethyl-butyl, 1,1,2-trimethyl-propyl, 1,2,2- Attorney Docket No.103361-086WO1 trimethyl-propyl, 1-ethyl-1-methyl-propyl, and 1-ethyl-2-methyl-propyl. Alkyl substituents may be unsubstituted or substituted with one or more chemical moieties. The alkyl group can be substituted with one or more groups including, but not limited to, hydroxy, halogen, acyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiosulfonate (e.g., -SSO2Ra), or thiol, as described below, provided that the substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied. The alkyl group can also include one or more heteroatoms (e.g., from one to three heteroatoms) incorporated within the hydrocarbon moiety. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” specifically refers to an alkyl group that is substituted with one or more halides (halogens; e.g., fluorine, chlorine, bromine, or iodine). The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “alkylamino” specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like. The term “alkylthiol” specifically refers to an alkyl group that is substituted with one or more thiol groups, as described below, and the like. When “alkyl” is used in one instance and a specific term such as “alkylalcohol” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “alkylalcohol” and the like. This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term. Attorney Docket No.103361-086WO1 As used herein, the term “alkenyl” refers to unsaturated, straight-chained, or branched hydrocarbon moieties containing a double bond. Unless otherwise specified, C2- C24 (e.g., C2-C22, C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, C2-C4) alkenyl groups are intended. Alkenyl groups may contain more than one unsaturated bond. Examples include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2- propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1- butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2- propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2- methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2- methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2- methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2- methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3- butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2- dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3- butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2- butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2- trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, and 1- ethyl-2-methyl-2-propenyl. The term “vinyl” refers to a group having the structure – CH=CH2; 1-propenyl refers to a group with the structure–CH=CH-CH3; and 2- propenyl refers to a group with the structure –CH2-CH=CH2. Asymmetric structures such as (Z1Z2)C=C(Z3Z4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. Alkenyl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiosulfonate (e.g., -SSO2Ra), or thiol, as described below, provided that the substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied. Attorney Docket No.103361-086WO1 As used herein, the term “alkynyl” represents straight-chained or branched hydrocarbon moieties containing a triple bond. Unless otherwise specified, C2-C24 (e.g., C2-C22, C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, C2-C4) alkynyl groups are intended. Alkynyl groups may contain more than one unsaturated bond. Examples include C2-C6-alkynyl, such as ethynyl, 1-propynyl, 2-propynyl (or propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3- butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 1-methyl-2-pentynyl, 4- methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2- methyl-4-pentynyl, 3-methyl-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2- butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, and 1-ethyl-1-methyl-2-propynyl. Alkynyl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiosulfonate (e.g., -SSO2Ra), or thiol, as described below. As used herein, the term “aryl,” as well as derivative terms such as aryloxy, refers to groups that include a monovalent aromatic carbocyclic group of from 3 to 20 carbon atoms. Aryl groups can include a single ring or multiple condensed rings. In some embodiments, aryl groups include C6-C10 aryl groups. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl. In some embodiments, the aryl group can be a phenyl, indanyl or naphthyl group. The term “heteroaryl” is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. The term “non-heteroaryl,” which is included in the term “aryl,” defines a group that contains an aromatic group that does not contain a heteroatom. The aryl or heteroaryl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, cycloalkyl, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as Attorney Docket No.103361-086WO1 described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of aryl. Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl. The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term “heterocycloalkyl” is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein. The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein. The term “cyclic group” is used herein to refer to either aryl groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups), or both. Cyclic groups have one or more ring systems that can be substituted or unsubstituted. A cyclic group can contain one or more aryl groups, one or more non-aryl groups, or one or more aryl groups and one or more non-aryl groups. Attorney Docket No.103361-086WO1 As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-10 ring atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six- membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3- triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4- thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are Attorney Docket No.103361-086WO1 moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl has 4-10, 4-7 or 4-6 ring atoms with 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin- 3-yl ring is attached at the 3-position. The term “acyl” as used herein is represented by the formula –C(O)Z1 where Z1 can be a hydrogen, hydroxyl, alkoxy, alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. As used herein, the term “acyl” can be used interchangeably with “carbonyl.” Throughout this specification “C(O)” or “CO” is a short hand notation for C=O. As used herein, the term “alkoxy” refers to a group of the formula Z1-O-, where Z1 is unsubstituted or substituted alkyl as defined above. Unless otherwise specified, alkoxy groups wherein Z1 is a C1-C24 (e.g., C1-C22, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4) alkyl group are intended. Examples include methoxy, ethoxy, propoxy, 1-methyl-ethoxy, butoxy, 1-methyl-propoxy, 2-methyl-propoxy, 1,1-dimethyl- ethoxy, pentoxy, 1-methyl-butyloxy, 2-methyl-butoxy, 3-methyl-butoxy, 2,2-di-methyl- propoxy, 1-ethyl-propoxy, hexoxy, 1,1-dimethyl-propoxy, 1,2-dimethyl-propoxy, 1- methyl-pentoxy, 2-methyl-pentoxy, 3-methyl-pentoxy, 4-methyl-penoxy, 1,1-dimethyl- butoxy, 1,2-dimethyl-butoxy, 1,3-dimethyl-butoxy, 2,2-dimethyl-butoxy, 2,3-dimethyl- butoxy, 3,3-dimethyl-butoxy, 1-ethyl-butoxy, 2-ethylbutoxy, 1,1,2-trimethyl-propoxy, 1,2,2-trimethyl-propoxy, 1-ethyl-1-methyl-propoxy, and 1-ethyl-2-methyl-propoxy. The term “aldehyde” as used herein is represented by the formula —C(O)H. The terms “amine” or “amino” as used herein are represented by the formula — NZ1Z2, where Z1 and Z2 can each be substitution group as described herein, such as hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, Attorney Docket No.103361-086WO1 cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. “Amido” is —C(O)NZ1Z2. The term “carboxylic acid” as used herein is represented by the formula — C(O)OH. A “carboxylate” or “carboxyl” group as used herein is represented by the formula —C(O)O-. The term “ester” as used herein is represented by the formula —OC(O)Z1 or —C(O)OZ1, where Z1 can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. The term “ether” as used herein is represented by the formula Z1OZ2, where Z1 and Z2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. The term “ketone” as used herein is represented by the formula Z1C(O)Z2, where Z1 and Z2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. The term “halide” or “halogen” or “halo” as used herein refers to fluorine, chlorine, bromine, and iodine. The term “hydroxyl” as used herein is represented by the formula —OH. The term “nitro” as used herein is represented by the formula —NO2. The term “silyl” as used herein is represented by the formula —SiZ1Z2Z3, where Z1, Z2, and Z3 can be, independently, hydrogen, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2Z1, where Z1 can be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. The term “sulfonylamino” or “sulfonamide” as used herein is represented by the formula The term “thiol” as used herein is represented by the formula —SH. The term “thio” as used herein is represented by the formula —S—. Attorney Docket No.103361-086WO1 As used herein, Me refers to a methyl group; OMe refers to a methoxy group; and i-Pr refers to an isopropyl group. “R1,” “R2,” “R3,” “Rn,” etc., where n is some integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1 is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an amine group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group. The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents." The molecule can be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Example substituents within this context can include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, - NRaSO2Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, - SORa, - S(=O)2Ra, -OS(=O)2Ra and -S(=O)2ORa. Ra and Rb in this context can be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl. Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible stereoisomer or mixture of stereoisomer (e.g., each enantiomer, each diastereomer, each meso compound, a racemic mixture, or scalemic mixture). Abbreviations Outer mitochondrial membrane (OMM), PTEN-induced putative kinase 1 (PINK1), Ub-specific protease (USP), deubiquitinating enzymes (DUBs), Translocase of outer membrane 20 (TOM20), Antimycin A/Oligomycin (A/O), Wild-type (WT), Attorney Docket No.103361-086WO1 Knockout (KO), Tetramethylrhodamine (TMRM), Carbonyl cyanide-p- trifluoromethoxyphenylhydrazone (FCCP) Reference will now be made in detail to specific aspects of the disclosed materials, compounds, compositions, articles, and methods, examples of which are illustrated in the accompanying Examples and Figures. Methods of Treating Ubiquitin specific peptidase 30 (USP30) is a member of the ubiquitin-specific protease family. USP30 is a mitochondrial deubiquitinating (DUB) enzyme. The present disclosure provides methods for treating, ameliorating and/or preventing cardiomyopathy in a subject in need thereof. The method including administering an effective amount of a small molecule USP30 inhibitor to inhibit, decrease, or reduce USP30 expression/activity. It is understood and herein contemplated that inhibiting, decreasing, or reducing USP30 expression/activity can treat, ameliorate, and/or prevent cardiomyopathy. In one aspect, disclosed herein are methods of treating, ameliorating and/or preventing cardiomyopathy in a subject comprising administering to the subject an effective amount of a small molecule USP30 inhibitor to inhibit, decrease, or reduce USP30 expression/activity. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the cardiomyopathy is caused by a drug, a viral infection, coronary artery disease, or high blood pressure. In some embodiments, the cardiomyopathy is drug induced cardiomyopathy. In some embodiments, the drug induced cardiomyopathy is caused by a drug selected from anthraquinone, antipsychotic phenothiazine derivates, arnica herb, arsenic, amphetamine, anabolic-androgenic steroids, azidothymidine, anagrelide, catecholamines, cytarabine, clozapine, cobalt, cocaine, chloroquine, cyclophosphamide, diazoxide, anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), ethanol, imatinib, isoproterenol, ephedrine, melarsoprol, methamphetamine, methylphenidate, minoxidil, mitomycin, mitoxantrone, paclitaxel, pentamidine, stibogluconate, sunitinib, trastuzumab, tricyclic antidepressants, or zidovudine. In some embodiments, the drug is an anthracycline. In some embodiments, Attorney Docket No.103361-086WO1 the drug is doxorubicin. In some embodiments, the drug is doxorubicin. In some embodiments, the drug is epirubicin. In some embodiments, the drug is daunorubicin. In some embodiments, the drug is idarubicin. In some embodiments, the cardiomyopathy is caused by a viral infection, coronary artery disease, or high blood pressure. In some embodiments, the viral infection is caused by a virus selected from Coxsackie B and adenovirus, echoviruses, influenza H1N1, Epstein-Barr virus, rubella virus, varicella-zoster virus, mumps virus, measles virus, parvoviruses, yellow fever virus, dengue virus, polio virus, rabies virus and the viruses that cause hepatitis A virus and hepatitis C virus, and SARS-COV-2. In some embodiments, the viral infection is caused by SARS-COV-2. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula I or a pharmaceutically acceptable salt thereof; wherein: Y1-Y4 is C or N; R1’to R8’ and R11’ each independently represent a hydrogen, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, ether, and amine, an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl, or an optionally substituted 5 to 10 membered heteroaryl or aryl; one or more spirocyclic groups where R1’ is linked to R2’, R3’ is linked to R4’, R5’ is linked to R6’, or R8’ is linked to R7’, or R2’ is linked to R8’ to form an optionally substituted C3-C4 cycloalkyl ring, R6’ is linked to R7’ to form an optionally substituted C3-C4 cycloalkyl ring; D is -C=O, C(R8a)(R9a), wherein R8a and R9a each independently represent hydrogen, cyano, optionally substituted C1-C6 alkyl, a 5 or 6 membered heteroaryl or aryl ring or R8a and R4a together form a 3 to 6 membered heteroalkyl or cycloalkyl ring; Attorney Docket No.103361-086WO1 E is O, N(Rc), and -C(R13)(R14)-; R13 and R14 each independently represent hydrogen, halogen, cyano, hydroxyl, an optionally substituted C1-C3 alkyl or an optionally substituted C1-C3 alkoxy group, a 3 to 6 membered heterocyclyl, heteroaryl, cycloalkyl or aryl ring, and a spirocyclic group where R13 is linked to R13 or R14 is linked to R8’ or R11’ to form an optionally substituted C3-C4 cycloalkyl; Rc is selected from hydrogen, optionally substituted C1-C3 alkyl, C(O)R', S(O)2R', and a 3 to 6 membered heterocyclyl, heteroaryl, cycloalkyl or aryl ring via a C0-C3 alkylene linker; R' is selected from optionally substituted C1-C3 alkyl, and a 3 to 6 membered heterocyclyl, heteroaryl, cycloalkyl or aryl ring; n is 0 or 1; m is 0 or 1; R9 represents an optionally substituted C1-C3 alkyl or forms an optionally substituted 5 to 10 membered monocyclic or bicyclic heterocyclyl or heteroaryl ring with R10 wherein the ring optionally comprises one or more additional heteroatoms or R9 together with R8’ or R11’ forms an optionally further substituted 5 or 6 membered ring; R10 represents a hydrogen, an optionally substituted 3 to 11 membered monocyclic or bicyclic cycloalkyl or heterocyclyl ring or optionally substituted 5 to 11 membered monocyclic or bicyclic heteroaryl or aryl ring, or R10 forms an optionally substituted 5 to 11 membered monocyclic or bicyclic heterocyclyl or heteroaryl ring with R9 wherein the ring optionally comprises one or more additional heteroatoms, R10 can be substituted with R11 represents a substituted monocyclic, optionally substituted bicyclic or optionally substituted tricyclic 3 to 14 membered heteroaryl, heterocyclyl, cycloalkyl or aryl ring; V represents a covalent bond, -(C0-C3)-alkylene-N(R12)-(C0-C3)-alkylene or optionally substituted C1- C3 alkylene; R12 represents a hydrogen atom, an optionally substituted C1-C6 alkyl, a 4 to 10 membered heteroaryl, heterocyclyl, aryl or 3 to 8 membered cycloalkyl ring or forms an optionally substituted monocyclic or bicyclic heterocyclic ring with R9 with the proviso that when the ring is bicyclic it is not substituted with NH2; Attorney Docket No.103361-086WO1 L represents a covalent bond, -SO-, -SO2-, -C(O)-, -C(O) O-, -CONR10a-, - SO2NR10a-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C1-C6 alkylene-C(O)-, C2- C6 alkenylene-C(O)-, -C1-C6 alkylene- NR10aCO-, -C1-C6 alkylene-CONR10a-, optionally substituted C1-C6 alkylene or optionally substituted - C2-C5 alkenylene; M represents an optionally substituted 3 to 11 membered monocyclic or bicyclic cycloalkyl or heterocyclyl ring or optionally substituted 5 to 11 membered monocyclic or bicyclic heteroaryl or aryl ring; and R10a represents hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, when R10 and R9 together form an optionally substituted ring, the ring may be referred to as ring G. In such cases the compound may be of the formula: Formula Ia or a pharmaceutically acceptable salt thereof, wherein ring G is an optionally substituted monocyclic or bicyclic heteroaryl ring and wherein n, m, E, D, Y2 to Y4, and R1’-R8’ and R11’ are as described above for Formula I. In some embodiments, when R10 is a substituted 3 to 10 membered monocyclic or bicyclic cycloalkyl or heterocyclyl ring or a substituted 5 to 10 membered monocyclic or bicyclic heteroaryl or aryl ring, or when R10 and R9 together form a substituted ring G, then the ring can be substituted with one or more (e.g. one, two, three or four) of -Q1-(Ra)n, in particular one or two of-Q1-(Ra)n. The heteroaryl ring may comprise one or more (e.g. 1, 2 or 3) additional heteroatoms independently selected from nitrogen, oxygen and sulphur, in particular nitrogen. Examples of nitrogen containing heteroaryl rings include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl, furazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, 4H-quinolizinyl, quinolinyl, Attorney Docket No.103361-086WO1 isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, isoindolinyl, triazinyl, dihydrophyridinyl, quinoxalinyl, dihydropyrrolopyridinyl and dihydrobenzoxazinyl. The optionally substituted 5 to 10 membered nitrogen-containing monocyclic or bicyclic heterocyclyl or heteroaryl ring may be selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, purinyl, furazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, triazinyl, dihydrophyridinyl, quinoxalinyl, dihydrobenzoxazinyl, dihydropyrrolopyridinyl pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, morpholinyl, oxazolidinyl, oxazinanyl, indolinyl, isoindolinyl, piperazinyl, thiomorpholinyl, homopiperazinyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, thiazolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl. In all cases described herein, R10, ring G, and ring M may be unsubstituted or substituted with one or more -Q1-(Ra)n, wherein each occurrence of-Q1(Ra)n is the same or different, wherein; n is 0 or 1; Q1 represents halogen, cyano, oxo, nitro, -OR5a, -SR5a, -NR5aR6a, - CONR5aR6a, -NR5aCOR6a, -NR5aCONR6aR7a, - COR5a, -C(O)OR5a, -SO2R5a, -SO2NR5aR6a, -NR5aSO2R6a, -NR5aSO2NR6aR7a, -NR5aC(O)OR6a, optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally substituted -C2-C6 alkenyl, a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SO2-, -CO-, -C(O)O-, -CONR5a-, -NR5a-, - NR5aCO-, -NR5aCONR6a-, -SO2NR5a-, NR5aSO2-, -NR5aSO2NR6a-, -NR5aC(O)O-, - NR5aC(O)OR6a-, optionally substituted C1-C6 alkylene, optionally substituted -C1- C6 alkyleneoxy, or optionally substituted -C2-C6 alkenylene; Ra is an optionally substituted 3 to 10 membered monocyclic or bicyclic ring; R5a, R6a, R7a each independently represent hydrogen optionally substituted C1- C6 alkyl or optionally substituted C1-C6 alkylene. In some embodiments, R11’ is a halogen. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Attorney Docket No.103361-086WO1 Formula Ib or a pharmaceutically acceptable salt thereof; wherein m, E, D, Y2 to Y4, and R1’ to R11’ are as described above for Formula I. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula Ic or a pharmaceutically acceptable salt thereof; wherein D, Y2 to Y4, and R1’ to R11’ are as described above for Formula I. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula Id or a pharmaceutically acceptable salt thereof; Attorney Docket No.103361-086WO1 wherein Y1 to Y4, and R1’ to R11’ are as described above for Formula I. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula Id-1 or a pharmaceutically acceptable salt thereof; wherein Y1, Y3, Y4, R9 R10 and R11’ are as described above for Formula I; R1’ to R2’ and R5’ to R8’, each independently represent a hydrogen, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, ether, and amine, an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl, or an optionally substituted 5 to 10 membered heteroaryl or aryl; one or more spirocyclic groups where R1’ is linked to R2’, R5’ is linked to R6’, or R8’ is linked to R7’, or R2’ is linked to R8’ to form an optionally substituted C3-C4 cycloalkyl ring, R6’ is linked to R7’ to form an optionally substituted C3-C4 cycloalkyl ring. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula Id-2 or a pharmaceutically acceptable salt thereof; Attorney Docket No.103361-086WO1 wherein Y2 to Y4, R9, R10 and R11’ are as described above for Formula I; R3’ to R8’, each independently represent a hydrogen, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, ether, and amine, an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl, or an optionally substituted 5 to 10 membered heteroaryl or aryl; one or more spirocyclic groups where R3’ is linked to R4’, R5’ is linked to R6’, or R8’ is linked to R7’ to form an optionally substituted C3-C4 cycloalkyl ring, R6’ is linked to R7’ to form an optionally substituted C3-C4 cycloalkyl ring. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula Ia-1 or a pharmaceutically acceptable salt thereof; wherein G, Y1, Y3, Y4, and R11’ are as described above for Formula Ia; R1’ to R2’ and R5’ to R8’, each independently represent a hydrogen, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, ether, and amine, an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl, or an optionally substituted 5 to 10 membered heteroaryl or aryl; one or more spirocyclic groups where R1’ is linked to R2’, R5’ is linked to R6’, or R8’ is linked to R7’, or R2’ is linked to R8’ to form an optionally substituted C3-C4 cycloalkyl ring, R6’ is linked to R7’ to form an optionally substituted C3-C4 cycloalkyl ring. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Attorney Docket No.103361-086WO1 or a pharmaceutically acceptable salt thereof; wherein R1’ to R11’, Y1, Y2, Y3, and Y4 are as described above for Formula I. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: or a pharmaceutically acceptable salt thereof; wherein Y1, Y3, Y4, R9, R10, and R11’are as described above for Formula I; R1’ to R2’ and R5’ to R8’, each independently represent a hydrogen, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, ether, and amine, an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl, or an optionally substituted 5 to 10 membered heteroaryl or aryl; one or more spirocyclic groups where R1’ is linked to R2’, R5’ is linked to R6’, or R8’ is linked to R7’, or R2’ is linked to R8’ to form an optionally substituted C3-C4 cycloalkyl ring, R6’ is linked to R7’ to form an optionally substituted C3-C4 cycloalkyl ring. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Attorney Docket No.103361-086WO1 Formula Ii or a pharmaceutically acceptable salt thereof; wherein R11’, Y1, Y3, Y4, R9, D, L, and M are as described above for Formula I; R1’ to R2’ and R5’ to R8’ each independently represent a hydrogen, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, ether, and amine, an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl, or an optionally substituted 5 to 10 membered heteroaryl or aryl; one or more spirocyclic groups where R1’ is linked to R2’, R5’ is linked to R6’, or R8’ is linked to R7’, or R2’ is linked to R8’ to form an optionally substituted C3-C4 cycloalkyl ring, R6’ is linked to R7’ to form an optionally substituted C3-C4 cycloalkyl ring. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula Ij or a pharmaceutically acceptable salt thereof; wherein m, E, Y1, Y3, Y4, R9, R11, R11’ and V, are as described above for Formula I; R1’ to R2’ and R5’ to R8’ each independently represent a hydrogen, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (C1- Attorney Docket No.103361-086WO1 C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, ether, and amine, an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl, or an optionally substituted 5 to 10 membered heteroaryl or aryl; one or more spirocyclic groups where R1’ is linked to R2’, R5’ is linked to R6’, or R8’ is linked to R7’, or R2’ is linked to R8’ to form an optionally substituted C3-C4 cycloalkyl ring, R6’ is linked to R7’ to form an optionally substituted C3-C4 cycloalkyl ring. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula II or a pharmaceutically acceptable salt thereof; wherein: A is an aryl; R3 to R6 are each independently selected from hydrogen, deuterium, (C1-C4)alkyl, (C1-C4)alkoxy and cycloalkoxy and halogen; and m is 0 or 1; E is -C(R12)(R13)-; Y1-Y4 is C or N; R1’to R8’ and each independently represent a hydrogen, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, ether, and amine, an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl, or an optionally substituted 5 to 10 membered heteroaryl or aryl; one or more spirocyclic groups where R1’ is linked to R2’, R3’ is linked to R4’, R5’ is linked to R6’, or R8’ is linked to R7’, or R2’ is linked to R8’ to form an optionally substituted C3-C4 cycloalkyl ring, R6’ is linked to R7’ to form an optionally substituted C3-C4 cycloalkyl ring. Attorney Docket No.103361-086WO1 In some embodiments, A is selected from: wherein: R2 is selected from hydrogen and alkyl; X, Y, and Z are each independently N, O, or C; wherein either: (i) X1 is CH; one of X2 and X3 is CR7, and the other is N; or (ii) X1 is CH or N; X2 is N; and X3 is CR8 or N; and R7 and R8 are each independently selected from hydrogen, halogen, (C1- C3)alkyl and (C1-C3)alkoxy. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer thereof, wherein: A is an aryl; R1 is selected from (C1-C4)alkyl, (C1-C4)haloalkyl, ether, and amine; R3, R4 and R5 are each independently selected from hydrogen, deuterium, and halogen; and Attorney Docket No.103361-086WO1 R6 is selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkoxy and cycloalkoxy. In some embodiments, A is selected from: wherein: R2 is selected from hydrogen and alkyl; X, Y, and Z are each independently N, O, or C; wherein either: (i) X1 is CH; one of X2 and X3 is CR7, and the other is N; or (ii) X1 is CH or N; X2 is N; and X3 is CR8 or N; and R7 and R8 are each independently selected from hydrogen, halogen, (C1- C3)alkyl and (C1-C3)alkoxy. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula IIb wherein: R1 is selected from (C1-C4)alkyl, (C1-C4)haloalkyl, ether, and amine; R3, R4 and R5 are each independently selected from hydrogen, deuterium, and halogen; and Attorney Docket No.103361-086WO1 R6 is selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkoxy and cycloalkoxy. R2 is selected from hydrogen and alkyl; X is N, O, or C. In some embodiments, X is C. In some embodiments, X is C, R1 is selected from (C1-C4)alkyl, (C1-C4)fluoroalkyl, CH2OCH3 and CH2N(CH3)2; R2 is selected from hydrogen and methyl; and R3, R4, R5 and R6 are each independently selected from hydrogen, deuterium and fluorine. In some embodiments, X is N. In some embodiments, X is N, R1 is selected from (C1-C4)alkyl, (C1-C4)fluoroalkyl and CH2OCH3; R3, R4 and R5 are each independently selected from hydrogen and fluorine; and R6 is selected from hydrogen, fluorine, (C1- C4)alkoxy and cyclopropoxy. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: wherein: R1 is selected from (C1-C4)alkyl, (C1-C4)haloalkyl, ether, and amine; R3, R4 and R5 are each independently selected from hydrogen, deuterium, and halogen; and R6 is selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkoxy and cycloalkoxy. wherein either: (i) X1 is CH; one of X2 and X3 is CR7, and the other is N; or (ii) X1 is CH or N; X2 is N; and X3 is CR8 or N; and Attorney Docket No.103361-086WO1 R7 and R8 are each independently selected from hydrogen, halogen, (C1- C3)alkyl and (C1-C3)alkoxy. In some embodiments, R1 is selected from (C1-C4)alkyl, (C1-C4)haloalkyl and CH2OCH3. In some embodiments, R3, R4 and R5 are each independently selected from hydrogen and deuterium. In some embodiments, R6 is selected from hydrogen, deuterium and fluorine. In some embodiments, R7 and R8 are each independently selected from hydrogen, halogen, (C1-C3)alkyl and (C1-C3)alkoxy. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula III or a pharmaceutically acceptable salt thereof; wherein R1’ to R11’, Y1, Y2, and Y3 are as described above for Formula I; wherein ring T is an optionally substituted monocyclic or bicyclic heteroaryl ring. The ring T can be substituted with one or more (e.g. one, two, three or four) of -Q1- (Ra)n, in particular one or two of-Q1-(Ra)n. The heteroaryl ring may comprise one or more (e.g. 1, 2 or 3) additional heteroatoms independently selected from nitrogen, oxygen and sulphur, in particular nitrogen. Examples of nitrogen containing heteroaryl rings include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl, furazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, isoindolinyl, triazinyl, dihydrophyridinyl, quinoxalinyl, dihydropyrrolopyridinyl and dihydrobenzoxazinyl. Attorney Docket No.103361-086WO1 The optionally substituted 5 to 10 membered nitrogen-containing monocyclic or bicyclic heterocyclyl or heteroaryl ring may be selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, purinyl, furazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, triazinyl, dihydrophyridinyl, quinoxalinyl, dihydrobenzoxazinyl, dihydropyrrolopyridinyl pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, morpholinyl, oxazolidinyl, oxazinanyl, indolinyl, isoindolinyl, piperazinyl, thiomorpholinyl, homopiperazinyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, thiazolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl. In all cases described herein, ring T may be unsubstituted or substituted with one or more -Q1-(Ra)n, wherein each occurrence of-Q1(Ra)n is the same or different, wherein; n is 0 or 1; Q1 represents halogen, cyano, oxo, nitro, -OR5a, -SR5a, -NR5aR6a, - CONR5aR6a, -NR5aCOR6a, -NR5aCONR6aR7a, - COR5a, -C(O)OR5a, -SO2R5a, -SO2NR5aR6a, -NR5aSO2R6a, -NR5aSO2NR6aR7a, -NR5aC(O)OR6a, optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally substituted -C2-C6 alkenyl, a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SO2-, -CO-, -C(O)O-, -CONR5a-, -NR5a-, - NR5aCO-, -NR5aCONR6a-, -SO2NR5a-, NR5aSO2-, -NR5aSO2NR6a-, -NR5aC(O)O-, - NR5aC(O)OR6a-, optionally substituted C1-C6 alkylene, optionally substituted -C1- C6 alkyleneoxy, or optionally substituted -C2-C6 alkenylene; Ra is an optionally substituted 3 to 10 membered monocyclic or bicyclic ring; R5a, R6a, R7a independently represent hydrogen optionally substituted C1- C6 alkyl or optionally substituted C1-C6 alkylene. In some embodiments, ring T can be a 5 membered nitrogen-containing aromatic ring optionally substituted with at least one optionally substituted 5 to 10 membered monocyclic or bicyclic heteroaryl or aryl ring. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Attorney Docket No.103361-086WO1 wherein R1’ to R16’, Y1, Y2, and Y3 are as described above for Formula I; wherein X1a, X1b, X1c, and X1d can be each independently N, CH, or one or more - Q1-(Ra)n, wherein each occurrence of-Q1(Ra)n is the same or different, wherein; n is 0 or 1; Q1 represents halogen, cyano, oxo, nitro, -OR5a, -SR5a, -NR5aR6a, - CONR5aR6a, -NR5aCOR6a, -NR5aCONR6aR7a, - COR5a, -C(O)OR5a, -SO2R5a, -SO2NR5aR6a, -NR5aSO2R6a, -NR5aSO2NR6aR7a, -NR5aC(O)OR6a, optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally substituted -C2-C6 alkenyl, a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SO2-, -CO-, -C(O)O-, -CONR5a-, -NR5a-, - NR5aCO-, -NR5aCONR6a-, -SO2NR5a-, NR5aSO2-, -NR5aSO2NR6a-, -NR5aC(O)O-, - NR5aC(O)OR6a-, optionally substituted C1-C6 alkylene, optionally substituted -C1- C6 alkyleneoxy, or optionally substituted -C2-C6 alkenylene; Ra is an optionally substituted 3 to 10 membered monocyclic or bicyclic ring; R5a, R6a, R7a each independently represent hydrogen optionally substituted C1- C6 alkyl or optionally substituted C1-C6 alkylene. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula IIIb wherein R1’, R2’, R5’, R6’, Y1, and Y3 are as described above for Formula I; Attorney Docket No.103361-086WO1 wherein X1a, X1b, X1c, and X1d can be each independently N, CH, or one or more - Q1-(Ra)n, wherein each occurrence of-Q1(Ra)n is the same or different, wherein; n is 0 or 1; Q1 represents halogen, cyano, oxo, nitro, -OR5a, -SR5a, -NR5aR6a, - CONR5aR6a, -NR5aCOR6a, -NR5aCONR6aR7a, - COR5a, -C(O)OR5a, -SO2R5a, -SO2NR5aR6a, -NR5aSO2R6a, -NR5aSO2NR6aR7a, -NR5aC(O)OR6a, optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally substituted -C2-C6 alkenyl, a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SO2-, -CO-, -C(O)O-, -CONR5a-, -NR5a-, - NR5aCO-, -NR5aCONR6a-, -SO2NR5a-, NR5aSO2-, -NR5aSO2NR6a-, -NR5aC(O)O-, - NR5aC(O)OR6a-, optionally substituted C1-C6 alkylene, optionally substituted -C1- C6 alkyleneoxy, or optionally substituted -C2-C6 alkenylene; Ra is an optionally substituted 3 to 10 membered monocyclic or bicyclic ring; R5a, R6a, R7a each independently represent hydrogen optionally substituted C1- C6 alkyl or optionally substituted C1-C6 alkylene. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula IV or a pharmaceutically acceptable salt thereof; wherein: E is O, N(Rc), and -C(R13)(R14)-; R13 and R14 each independently represent hydrogen, halogen, cyano, hydroxyl, an optionally substituted C1-C3 alkyl or an optionally substituted C1-C3 alkoxy group, a 3 to 6 membered heterocyclyl, heteroaryl, cycloalkyl or aryl ring, and a spirocyclic group where R13 is linked to R13 or R14 is linked to R8’ or R11’ to form an optionally substituted C 3 -C 4 cycloalkyl; Rc is selected from hydrogen, optionally substituted C1-C3 alkyl, C(O)R', S(O)2R', and a 3 to 6 membered heterocyclyl, heteroaryl, cycloalkyl or aryl ring via a C0-C3 alkylene linker; Attorney Docket No.103361-086WO1 R' is selected from optionally substituted C1-C3 alkyl, and a 3 to 6 membered heterocyclyl, heteroaryl, cycloalkyl or aryl ring. Y1 and Y3 is C or N; R1’to R8’ and each independently represent a hydrogen, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, ether, and amine, an optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl, or an optionally substituted 5 to 10 membered heteroaryl or aryl; one or more spirocyclic groups where R1’ is linked to R2’, R3’ is linked to R4’, R5’ is linked to R6’, or R8’ is linked to R7’, or R2’ is linked to R8’ to form an optionally substituted C3-C4 cycloalkyl ring, R6’ is linked to R7’ to form an optionally substituted C3-C4 cycloalkyl ring; M represents an optionally substituted 3 to 11 membered monocyclic or bicyclic cycloalkyl or heterocyclyl ring or optionally substituted 5 to 11 membered monocyclic or bicyclic heteroaryl or aryl ring; ring M may be unsubstituted or substituted with one or more -Q1-(Ra)n, wherein each occurrence of- the same or different, wherein; n is 0 or 1; Q1 represents halogen, cyano, oxo, nitro, -OR5a, -SR5a, -NR5aR6a, - CONR5aR6a, -NR5aCOR6a, -NR5aCONR6aR7a, - COR5a, -C(O)OR5a, -SO2R5a, -SO2NR5aR6a, -NR5aSO2R6a, -NR5aSO2NR6aR7a, -NR5aC(O)OR6a, optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally substituted -C2-C6 alkenyl, a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SO2-, -CO-, -C(O)O-, -CONR5a-, -NR5a-, - NR5aCO-, -NR5aCONR6a-, -SO2NR5a-, NR5aSO2-, -NR5aSO2NR6a-, -NR5aC(O)O-, - NR5aC(O)OR6a-, optionally substituted C1-C6 alkylene, optionally substituted -C1- C6 alkyleneoxy, or optionally substituted -C2-C6 alkenylene; Ra is an optionally substituted 3 to 10 membered monocyclic or bicyclic ring; R5a, R6a, R7a each independently represent hydrogen optionally substituted C1- C6 alkyl or optionally substituted C1-C6 alkylene. The heteroaryl ring may comprise one or more (e.g. 1, 2 or 3) additional heteroatoms independently selected from nitrogen, oxygen and sulphur, in particular nitrogen. Examples of nitrogen containing heteroaryl rings include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl, furazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzimidazolyl, Attorney Docket No.103361-086WO1 benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, isoindolinyl, triazinyl, dihydrophyridinyl, quinoxalinyl, dihydropyrrolopyridinyl and dihydrobenzoxazinyl. The optionally substituted 5 to 10 membered nitrogen-containing monocyclic or bicyclic heterocyclyl or heteroaryl ring may be selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, purinyl, furazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, triazinyl, dihydrophyridinyl, quinoxalinyl, dihydrobenzoxazinyl, dihydropyrrolopyridinyl pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, morpholinyl, oxazolidinyl, oxazinanyl, indolinyl, isoindolinyl, piperazinyl, thiomorpholinyl, homopiperazinyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, thiazolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula V or a pharmaceutically acceptable salt thereof; wherein: l is 0 or 1 and p is 0 or 1, wherein at least one of l or p is 1; n is 0 or 1; R1’to R8’ and R11’ each independently represent a hydrogen, halogen, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, ether, and amine, an Attorney Docket No.103361-086WO1 optionally substituted 3 to 10 membered cycloalkyl or heterocyclyl, or an optionally substituted 5 to 10 membered heteroaryl or aryl; one or more spirocyclic groups where R1’ is linked to R2’, R3’ is linked to R4’, R5’ is linked to R6’, or R8’ is linked to R7’, or R2’ is linked to R8’ to form an optionally substituted C3-C4 cycloalkyl ring, R6’ is linked to R7’ to form an optionally substituted C3-C4 cycloalkyl ring; R14 and R15are selected from hydrogen, (C1-C6)alkyl, and (C1-C6)alkoxy(C1- C6)alkyl, an optionally substituted ring, or R15 together with R14 forms an optionally further substituted ring; or R14 together with A’ forms an optionally substituted heterocyclyl or heteroaryl ring; L1 is selected from a covalent bond, an optionally substituted (C1-C4)alkylene, and an optionally substituted (C2-C4)alkenylene, or forms part of an optionally substituted heterocyclyl or heteroaryl ring with A’; L2 is selected from a covalent bond, (C1-C4)alkylene, (C2-C4)alkenylene, and (C0-C3)alkylene-X-(C0-C3)alkylene, or forms part of an optionally substituted heterocyclyl or heteroaryl ring with B’; X’ is selected from O, S, SO, SO2, NR4, NR4C(O), C(O)NR4, NR4C(O) NR5, C(O), C(O)O, OC(O), OC(O)O, SO2NR4, NR4SO2, and NR4SO2NR5; R4 and R5 are each independently selected from hydrogen, (C1-C6)alkyl, and (C1-C6)alkoxy(C1-C6)alkyl; A’ is selected from hydrogen, optionally substituted C1-C6 alkyl, an optionally substituted, 3 to 10-membered carbocyclic ring, and a 3 to 10-membered heterocyclic ring comprising 1 to 4 heteroatoms independently selected from N, O, and S, or A’ together with R14 forms an optionally substituted heterocyclyl or heteroaryl ring; and B’ is selected from a 3 to 10-membered carbocyclic ring, and a 3 to 10-membered heterocyclic ring comprising 1 to 4 heteroatoms independently selected from N, O, and S; and each carbocyclic and heterocyclic ring may be optionally substituted with 1 to 4 substituents independently selected from halo, cyano, hydroxy, oxo, (C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, NH(C1- C6)alkyl, N((C1-C6)alkyl)2, C(O)NH(C1-C6)alkyl, C(O)N((C1-C6)alkyl)2, NHC(O)(C1- C6)alkyl, N(C1-C6)alkyl)C(O)(C1-C6)alkyl), C(O)(C1-C6)alkyl, C(O)O(C1-C6)alkyl, CO2H, CONH2, SO2NH(C1-C6)alkyl, and SO2N((C1-C6)alkyl)2. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Attorney Docket No.103361-086WO1 Formula Va or a pharmaceutically acceptable salt thereof; wherein A’, L1, R14, R15, Y1 to Y4, E and m are as described above for Formula V. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula Vb or a pharmaceutically acceptable salt thereof; wherein A’, L1, B’, L2, R14, Y1 to Y4, E and m are as described above for Formula V. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula Vc Attorney Docket No.103361-086WO1 or a pharmaceutically acceptable salt thereof; wherein A’, L1, B’, L2, R15, Y1 to Y4, E and m are as described above for Formula V. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula Vd or a pharmaceutically acceptable salt thereof; wherein A’, L1, R14, R15, Y1, and Y3 to Y4 are as described above for Formula V. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula Ve or a pharmaceutically acceptable salt thereof; wherein A’, L1, B’, L2, R14, Y1, and Y3 to Y4 are as described above for Formula V. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Attorney Docket No.103361-086WO1 Formula Vf or a pharmaceutically acceptable salt thereof; wherein A’, L1, B’, L2, R15, Y1, and Y3 to Y4 are as described above for Formula V. In some embodiments, the small molecule USP30 inhibitor can be defined by the formula: Formula VI wherein, A’ is a substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl; and B’ is a substituted or unsubstituted -(alkylene)-aryl or a substituted or unsubstituted - (alkylene) -heteroaryl. Other examples of suitable small molecule USP30 inhibitors may be found, e.g., in PCT publication Nos. WO2021043870A1, WO2020212350A1, WO2020212351A1, WO2016046530A1, WO 2017/009650, WO 2017/109488, WO 2017/141036, WO2018060742A1, WO 2017/149313, WO 2017/158381, WO2017158388A1, WO 2017/103614, WO2016156816A1, WO2018065768A1, WO 2017/163078, WO2019071073A1, WO2020072964A1, WO2018060691A1, WO2018060689A1, WO 2017/093718, WO2018220355A1, WO 2018/213150, WO 2015/183987, WO2012040527A2, and WO 01/77073; and U.S. Patent Publication No. US20210002262A1. Attorney Docket No.103361-086WO1 Combination Therapies The small molecule USP30 inhibitors as described herein may be administered in combination with other therapies such as, for example, radiation therapy, surgery, conventional chemotherapy, or with a combination of one or more additional therapies. The methods and small molecule USP30 inhibitors derived from this invention may be administered alone in a pharmaceutical composition or combined with therapeutically effective and physiologically acceptable amount of one or more other active ingredients or agents. Such other active ingredient includes, but is not limited to chemotherapeutic agent(s). The small molecule USP30 inhibitors described in herein may be administered in combination with other therapies simultaneously or sequentially. The separation in time between administrations may be minutes, hours, days or it may be longer. For example, the small molecule USP30 inhibitors described herein can be administered before, after, or simultaneously with chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy such as anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone). In some embodiments, additional chemotherapeutic agents can be administered before, after, or simultaneously with the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy. Additional, chemotherapeutic agents such as alkylating agents (e.g. , chlorambucil, cyclophosphamide, ccnu, melphalan, procarbazine, thiotepa, bcnu, and busulfan), DQWLPHWDEROLWHV^^H^J^^^^^^^PHUFDSWRSXULQH^DQG^^^IOXRURXUDFLO^^^DQWLWXPRU^DQWLELRWLFV^^H^J^^^^ bleomycin), monoclonal antibodies (e.g., alemtuzumab, bevacizumab, cetuximab, gemtuzumab, ibritumomab, panitumumab, rituximab, tositumomab, and trastuzumab), platinums (e.g. , cisplatin, oxaliplatin, and carboplatin), plant alkaloids (e.g. , vincristine), topoisomerase I or II inhibitors (e.g. , irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide), vinca alkaloids (e.g. , vincristine, vinblastine, vinorelbine, and vindesine), taxanes (e.g. , paclitaxel and docetaxel), epipodophyllotoxins (e.g. , etoposide and teniposide), nucleoside analogs, and angiogenesis inhibitors (e.g. , Avastin (EHUDFL]XPDE^^^D^KXPDQL]HG^PRQRFORQDO^DQWLERG\^VSHFLILF^IRU^9(*)^$^^^ Examples of glutathione antagonists include but are not limited to buthionine sulfoximine, F\FORSKRVSKDPLGH^^LIRVSKDPLGH^^DFWLQRP\FLQ^G^DQG^1^^^^K\GUR[\SKHQ\O^^UHWLQDPLGH^^^^ HPR). Examples RI^DQJLRJHQHVLV^LQKLELWRUV^LQFOXGH^EXW^DUH^QRW^OLPLWHG^WR^^^ PHWKR[\HVWUDGLRO^^^0(^^^$*^^^^^^$QJLRVWDWLQ^^DQWLWKURPELQ^,,,^^$QWL^^9(*)^DQWLERG\^^ Attorney Docket No.103361-086WO1 %DWLPDVWDW^^EHYDFL]XPDE^^$YDVWLQ^^^%06^^^^^^^^^^&$^^^^&DQVWDWLQ^^FRPEUHWDVWDWLQ^^ &RPEUHWDVWDWLQ^$^^SKRVSKDWH^^&&^^^^^^^FDSWRSULO^^FHOHFR[LE^^'DOWHSDULQ^^(0'^^^^^^^^ Endostatin, Erlotinib, Gefitinib, Genistein, Halofuginone, ID 1 , ID3, IM862, Imatinib PHV\ODWH^^,QGXFLEOH^SURWHLQ^^^^^^,QWHUIHURQ^^DOSKD^^,QWHUOHXNLQ^^^^^/DYHQGXVWLQ^D^^ /<^^^^^^^^RU^$(^^^^^^^0DULPDVWDW^ 0DSVLQ^^0HGUR[\SURJHVWHURQH^DFHWDWH^^0HWK^^^^^ 0HWK^^^^1HRYDVWDW^^2VWHRSRQWLQ^FOHDYHG^SURGXFW^^3(;^^3LJPHQW^HSLWKHOLXP^JURZWK^IDFWRU^ ^3(*)^^^SODWHOHW^JURZWK^IDFWRU^^^^SURODFWLQ^IUDJPHQW^^SUROLIHULQ^UHODWHG^SURWHLQ^353^^^ PTK787/ZK222584, recombinant human pODWHOHW^IDFWRU^^^U3)^^^^UHVWLQ^^VTXDODPLQH^^ SU5416, SU6668, Suramin, Taxol, Tecogalan, Thalidomide, Tetrathiomolybdate (TM), 7KURPERVSRQGLQ^^713^^^^^^7URSRQLQ^,^^9DVRVWDWLQ^^9(*)^^^^9(*)^73Y$3^DQG^='^^^^^^ In some embodiment the angiogenesis inhibitor is a VRGF antagonist. The VEGF antagonist may be a VEGF binding molecule. VEGF binding molecule include VEGF antibodies, or antigen binding fragment (s) thereof. One example of a VEGF antagonist is NeXstar. Chemotherapeutic agents that can be combined with the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy disclosed herein include, but are not limited to, DNA damaging agents and these include topoisomerase inhibitors (e.g., etoposide, camptothecin, topotecan, irinotecan, teniposide, PLWR[DQWURQH^^^DQWL^^PLFURWXEXOH^DJHQWV (e.g. , vincristine, vinblastine), antimetabolite DJHQWV^^H^J^^^^F\WDUDELQH^^PHWKRWUH[DWH^^K\GUR[\XUHD^^^^IOXRURXUDFLO^^IORXULGLQH^^^^ WKLRJXDQLQH^^^^PHUFDSWRPSXULQH^^IOXGDUDELQH^^SHQWRVWDWLQ, chlorodeoxyadenosine), DNA alkylating agents (e.g. , cisplatin, mecholorethamine, cyclophosphamide, ifosphamide, melphalan, chlorambucil, busulfan, thiotepa, carmustine, lomustine, carboplatin, dacarbazine, procarbazine) and DNA strand break inducing agents( e.g. , bleomycin, doxorubicin, daunorubicin, idarubicin, mitomycin C). Other chemotherapeutic agents that can be combined with the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy described herein include: synthetic, semisynthetic and naturally derived agents. Important chemotherapeutic agents include, but are not limited to, Avicine, Aclarubicin, Acodazole, Acronine, Adozelesin, Adriamycin, aldesleukin, Alitretinoin, AUopurinol sodium, Altretamine, Ambomycin, Ametantrone acetate, Aminoglutethimide, Amsacrine, Anastrazole, Annonaceous Acetogenins, Anthramycin, Asimicin, Asparaginase, asperlin, Azacitidine, azetepa, Azotomycin, batimastat, benzodepa, bexarotene, Bicalutamide, Attorney Docket No.103361-086WO1 Bisantrene, Bisnafide, Bizelesin, Bleomycin, Brequinar, Bropirimine, Bullatacin, Busulfan, Cabergoline, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin, carzelesin, cedefingol, chlorambucil, celecoxib, cirolemycin, cisplatin, cladribine, crisnatol, cyclophosphamide, cytarabine, dacarbazine, DACA, dactinomycin, Daunorubicin, daunomycin, Decitabine, denileukin, Dexormaplatin, Dezaguanine, Diaziquone, Docetaxel, Doxorubicin, Droloxifene, Dromostalone, Duazomycin, Edatrexate, Eflornithine, Elsamitrucin, Estramustine, Etanidazole, Etoposide, Etoprine, Fadrozole, Fazarabine, Fenretinide, Floxuridine, Fludarabine, )OXRURXUDFLO^^)OXURFLWDELQH^^^^)G803^^)RVTXLGRQH^^)RVWHXHFLQH^^).^^^^^^).^^^^^^)5^ ^^^^^^^)5^^^^^^^^^*HPFLWDELQH^^*HPWX]XPDE^^2]RJDPLFLQ^^*ROG Aul 98, Goserelin, Guanacone, Hydroxyurea, Idarubicin, Ilmofosine, Interferon alpha and analogs, Iproplatin, irinotecan, Lanreotide, Letrozole, Leuprolide, Liarozole, Lometrexol, Lomustine, Losoxantrone, masoprocol, Maytansine, Mechlorethamine, Megestrol, Melengestrol, Melphalan, Menogaril, Metoprine, maturedepa, mitindomide, Mitocarcin, Mitogillin, Mitomalacin, Mitomycin, Mitomycin C, Mitosper, Mitotane, Mitoxantrone, Mycophenolic acid, Nocodazole, Nogalamycin, Oprelvekin, ormaplatin, Oxisuran, Paclitaxel, pamidronate, pegaspargase, Peliomycin, Pentamustine, Peplomycin, Perfosfamide, Pipobroman, Piposulfan, Piroxantrone, Plicamycin, Plomestane, Porfimer, Porfiromycin, Prednimustine, procarbazine, Puromycin, Pyrazofurin, Riboprine, Rituximab, Rogletimide, Rolliniastatin, safingol, Samarium, Semustine, Simtrazene, Sparfosate, Sparsomycin, spirogermanium, Spiromustine, Spiroplatin, Squamocin, Squamotacin, streptonigrin, streptozocin, SrC12, Sulphofenur, Talisomycin, Taxane, Toxoid, Tecoglan, Tegafur, teloxantrone, Temoporfin, teniposide, Teroxirone, Testolactone, Thiamiprine, 7KLRWHSD^^7K\PLWDT^^7LD]RIXULQ^^7LUDSD]DPLQH^^7RPXGH[^^7RS^^^^^7RSRWHFDQ^^ Toremixifme, Trastuzumab, Trestolone, triciribine, Triciribine, Trimetrexate, trimetrexate glucuronate, Triptorelin, Tubulozole, uracil mustard, Uredepa, valrubicin, vapreotide, Vinblastine, Vincristine, Vindesine, Vinepidine, Vinglycinate, Vinleurosine, Vinorelbine, 9LQURVLGLQH^^9LQ]ROLGLQH^^9RUR]ROH^^=HQLSODWLQ^^=LQRVWDWLQ^^=RUXELFLQ^^^^ chROURGHR[\UXELFLQH^^^^^GHR[\IRUP\FLQ^^^^DPLQRFDPSWRWKHFLQ^^UDOWLWUH[HG^^1^SURSDUJ\O^ ^^^^GLGH]DIROLF DFLG^^^^FKROR^^^DUDELQRIOXRUR^^^^GHR[\DGHQRVLQH^^^^FKROR^^^^^ deoxyadenosine, anisomycin, Trichostatin, K35/^*^^^5^^&(3^^^^^^/LQRPLGH^^6XOIXU^ mustard, nitrogeQ^PXVWDUG^^1^PHWK\O^1^QLWURVRXUHD^ fotemustine, Streptozotocin, GDFDUED]LQH^^PLWR]RORPLGH^^WHPR]RORPLGH^^$=4^^RUPDSODWLQ^^&,^^^^^ DWA2114R, Attorney Docket No.103361-086WO1 -0^^^^^-0^^^^^%LVSODWLQXP^^7RPXGH[^^D]DFLWLGLQH^^F\WUDELQFLQH^^JHPFLWDELQH^^^^ mercaptopurine, Hypoxanthine, TeniposLGH^^&37^^^^^^^'R[RUXELFLQ^^'DXQRUXELFLQ^^ Epirubicin, darubicin, ORVR[DQWURQH^^DPVDFULQH^^S\UD]RORDFULGLQH^^DOO^WUDQV^UHWLQRO^^^^^^ K\GUR[\^UHWUR^UHWLQRO^^DOO^WUDQV^UHWLQRLF DFLG^^1^^^^K\GUR[\SKHQ\O^^UHWLQDPLGH^^^^^^ FLVUHWLQRLF^DFLG^^^^^PHWK\O^771(%^^^^FLVUetenoic acid, IOXGDUDELQH^^DQG^^^&GD^ Other chemotherapeutic agents that can be combined with the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy described herein LQFOXGH^^^^^HSLO^^^^GLK\GUR[\YLWDPLQ^'^^^^^HWK\Q\O^XUDFLO^^DELUDWHURQH^^ aclarubicin, acylfulvene, adecylpenol, adozelesin, DOGHVOHXNLQ^^$//^7.^DQWDJRQLVWV^^ altretamine, ambumastine, amidox, amifostine, amino levulinic acid, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonists D, antarelix, DQWL^GRUVDOL]LQJ^PRUSKRJHQHWLF^SURWHLQ^^^^^^DQWLDQGURJHQ^^DQWLHVWURJHQ^^ antineoplastone, antisense oligonucleotides, aphidicolin, apoptosis gene modulators, DSRSWRVLV^UHJXODWRUV^^DSXULQLF^DFLG^^DUD^FGS^GO^37%$^^DUJLQLQH^aminase, asulacrine, atamestine, atrimustine, axinamastine 1 and axinamastine 2, axinamastine 3, azasetron, azatoxin, azatyrosine, baccatin III derivatives, balanol, BCR/ABL antagonist, EHQ]RFKORULQV^^EHQ]R\OVDXURVSRULQH^^EHWD^ODFWDP^GHULYDWLYHV^^EHWD^DOHWhine. Perillyl alcohol, phenozenomyein, phenyl acetate, phosphatase inhibitors, picibanil, pilocarbine and salts or analogs thereof, pirarubucin, piritrexim, placetin A, placetin B, plasminogen activator inhibitor, platinum complex, phenyl ethyl isothiocyanate and analogs thereof, platinum compounds, platinum triamine complex, podophylotoxin, porfimer sodium, porphyromycin, propyl bis acridones, prostaglnadins J2, protease inhibitors, protein A based immune modulators, PKC inhibitors, microalgal, protein tyrosine phosphatase inhibitors, purine neucleoside phosphorylase inhibitors, purpurins, pyrazoloacridines, pyridoxylated haemoglobn polyoxyethylene conjugate, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein tranaferase inhibitors, rasinhibitoUV^^UDV^*$3^LQKLELWRUV^^ ratellitptine demethylated, Rhenium Re 186 etidronate, rhizoxine, ribozyme, RII retinide, rogletimide, rosagliatazone and analogs and derivatives thereof, rohitukine, romurtide, roquinimex, rubiginone Bl , ruboxyl, safingol, saintopin, SarCNU, sarcophytol A, sargrmostim, sdi 1 mimetics, semustine, senescence derived inhibitor 1 , sense oligonucleotide, signal transduction inhibitors, signal transduction modulators, single chain antigen binding protein, sizofiran, sobuzoxane, sodium borocaptate, sodium phenyl acetate, solverol, somatomedin binding protein, sonermin, sparfosic acid, spicamycin D, Attorney Docket No.103361-086WO1 spiromustin, splenopentine, spongistatin 1 , squalamine, stem cell inhibitor, stem cell division inhibitor, stipiamide, stromelysin, sulfinosine, superactive vasoactive intestinal peptide antagonists, suradista, siramin, swainsonine, synthetic glycosaminoglycans, tallimustine, tamoxifen methiodide, tauromustine, tazarotene, tacogalan sodium, tegafur, tellurapyrilium, telomerase inhibitors, temoporfin, tmeozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, thaliblastine, thalidomide, thiocoraline, thrombopoetin and mimetics thereof, thymalfasin, thymopoetin receptor agonist, thymotrinan, thyroid stimulating harmone, tin ethyl etiopurpin, tirapazamine, titanocene and salts thereof, topotecan, topsentin, toremifene, totipotent stem cell factors, translation inhibitors, tretinoin, triacetyluridine, tricribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, vector system, erythrocyte gene therapy, velaresol, veramine, verdins, verteporfin, vinorelbine, vinxaltine, vitaxin, vorozol, zanoterone, zeniplatin, zilascorb and zinostatin. Further chemotherapeutic agents that can be combined with the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy described herein include: antiproliferative agents (e.g., piritrexim isothiocyanate), antiprostatic hypertrophy agents(sitogluside), Benign prostatic hyperplasia therapy agents (e.g., tomsulosine, RBX2258), prostate growth inhibitory agents (pentomone) and radioactive agents: Fibrinogen 1125, fludeoxyglucose F18, Flurodopa F18, Insulin 1125, lobenguane 1123, lodipamide sodium 1131 , lodoantipyrine 1131 , Iodocholesterol 1131 , Iodopyracet 1125, Iofetamine HCL 1123, Iomethin 1131 , Iomethin 1131 , Iothalamate sodium 1125, Iothalamate 1131 , Iotyrosine 1131 , Liothyronine 1125, Merosproprol Hgl ^^^^0HWK\O^LRRGREHQ]RJXDQLQH^^0,%*^,^^^^RU^0,%*,^^^^^^^VHOHQRPHWKLRQLQH^6H^^^^ Technetium Tc99m furifosmin, technetium Tc99m gluceptate, Tc99m Biscisate, Tc99m disofenin, TC99m gluceptate, Tc99m lidofenin, Tc99m mebrofenin, Tc99m medronate and sodium salts thereof, Tc99m mertiatide, Tc99m oxidronate, Tc99m pentetate and salts thereof, Tc99m sestambi, Tc99m siboroxime, Tc99m succimer, Tc99m sulfur colloid, Tc 99m teboroxime, Tc 99m Tetrofosmin, Tc99m Tiatide, Thyroxine 1125, Thyroxine 1131 , Tolpovidone ^^^^^^^7ULROHLQ^^^^^^DQG^7UHROLQH^^^^^^^DQG^7UHROLQH^^^^^^^0,%*^,^^^^DQG^ MIBG 1131. In some embodiments, the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy described herein are administered in Attorney Docket No.103361-086WO1 combination with one or more immune checkpoint inhibitors, kinase inhibitors, tubulin inhibitors, or topoisomerase inhibitors. In some embodiments, the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy described herein are administered in combination with one or more immune checkpoint inhibitors. Immune checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Illustrative immune checkpoint targets for blocking or inhibition include, but are not limited to, &7/$^^^^3'/^^^3'/^^^3'^^^%^^+^^^ %^^+^^^%7/$^^+9(0^^*$/^^^/$*^^^7,0^^^9,67$^^.,5^^^%^^^EHORQJV^WR^WKH CD2 family of molecules and is expressed on all NK, Ȗį^^and memory CD8+ (Įȕ^^T cells), CD160 (also UHIHUUHG^WR^DV^%<^^^^^&*(1^^^^^^^^^&+.^^^DQG^&+.^^NLQDVHV^^$^D5^DQG^ YDULRXV^%^^^IDPLO\^OLJDQGV^^%^ IDPLO\^OLJDQGV^LQFOXGH^^EXW^DUH^QRW^OLPLWHG^WR^^%^^^^^%^^^^^ %^^'&^^%^^+^^^%^^+^^^%^^+^^^%^^+^^^%^^+^^^%^^+^^DQG^%^^+^^^,mmune checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics or small molecules, that bind to and block or inhibit the activity of one or more of &7/$^^^^3'/^^^3'/^^^3'^^^%7/$^^+9(0^^7,0^^^*$/^^^/$*^^^ 9,67$^^.,5^^^%^^^&'^^^^DQG^&*(1^^^^^^^ Illustrative immune checkpoint inhibitors LQFOXGH^7UHPHOLPXPDE^^&7/$^^^EORFNLQJ^DQWLERG\^^^DQWL^2;^^^^3'^/^^PRQRFORQDO $QWLERG\^^$QWL^%^^+^^^0(',^^^^^^^0.^^^^^^^3'^^^EORFNHU^^^1LYROXPDE^^DQWL^3'^^ DQWLERG\^^^&7^^^^ ^DQWL^3'^^DQWLERG\^^^%<^^^PRQRFORQDO^DQWLERG\^^$03^^^^^DQWL^3'/O^ DQWLERG\^^^%06^^^^^^^^^DQWL^3'/^ antibody), MPLDL3280$^^DQWL^3'/^^DQWLERG\^^^ 06%^^^^^^^&^^DQWL^3'/^^DQWLERG\^^DQG <HUYR\^LSLOLPXPDE^^DQWL^&7/$^^^FKHFNSRLQW^ inhibitor). Checkpoint protein ligands include, but are not OLPLWHG^WR^3'^/^^^3'^/^^^%^^ +^^^%^^+^^^&'^^^^&'^^^DQG^7,0^^^ In one embodiment, the present invention covers the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy of the present invention may be used with one or more additional therapeutics that block the interaction between immune checkpoint recHSWRU^SURJUDPPHG^FHOO^GHDWK^SURWHLQ^^^^3'^^^^ and its OLJDQG^3'^/O^^6HH^$^^0XOODUG^^^1HZ^FKHFNSRLQW^LQKLELWRUV^ULGH^WKH^LPPXQRWKHUDS\^ tsunami," Nature 5HYLHZV^^'UXJ^'LVFRYHU\^^^^^^^^^^^^^^^^^^^^^3'^^^LV^H[SUHVVHG^RQ^DQG^ UHJXODWHV^WKH^DFWLYLW\^RI^7^FHOOV^ SSHFLILFDOO\^^ZKHQ^3'^^^LV^XQERXQG^WR^3'/^^^^WKH^7^FHOOV^ can engage and kill target cells. However, when 3'^^^LV^ERXQG^WR^3'/^^^LW^FDXVHV^WKH^7^ cells to cease engaging and killing target cells. Furthermore, unlike RWKHU^FKHFNSRLQWV^^3'^ Attorney Docket No.103361-086WO1 1 acts proximately such the PDLs are overexpressed directly on cancer cells which leads WR^LQFUHDVHG^ELQGLQJ^WR^WKH^3'^^^H[SUHVVLQJ^7^FHOOV^ In another aspect, the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy of the present disclosure may be used in combination with DQWLERGLHV^WKDW^FDQ^DFW^DV^DJRQLVWV^RI^3'^^ and which thereby modulate LPPXQH^UHVSRQVHV^UHJXODWHG^E\^3'^^^^,Q^RQH^HPERGLPHQW^^WKH^DQWL^3'^^^DQWLERGLHV can be DQWLJHQ^ELQGLQJ^IUDJPHQWV^^$QWL^3'^^^DQWLERGLHV^GLVclosed herein are able to bind to KXPDQ^3'^^ DQG^DJRQL]H^WKH^DFWLYLW\^RI^3'^^^^WKHUHE\^LQKLELWLQJ^WKH^IXQFWLRQ^RI^LPPXQH^ FHOOV^H[SUHVVLQJ^3'^^^ In some embodiments, the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy of the present disclosure may be used in combination with one or more PD-1 inhibitors selected from pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, nivolumab, AMP-224, or AMP-514. In some embodiments, the compounds of the present disclosure may be used in combination with one or more PD-L1 inhibitors selected from atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, or BMS-986189. In some embodiments, the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy of the present disclosure may be used in combination with one or more therapeutic agents that inhibit &7/$^^^^6XLWDEOH^DQWL^ CTLA4 antagonist agents for use herein, include, without OLPLWDWLRQ^^DQWL^&7/$^^ DQWLERGLHV^^KXPDQ^DQWL^&7/$^^DQWLERGLHV^^PRXVH^DQWL^&7/$^^DQWLERGLHV^ mammalian DQWL^&7/$^^DQWLERGLHV^^KXPDQL]HG^DQWL^&7/$^^DQWLERGLHV^^PRQRFORQDO^DQWL^&7/$^ DQWLERGLHV^^SRO\FORQDO^DQWL^&7/$^^DQWLERGLHV^^FKLPHULF^DQWL^&7/$^^DQWLERGLHV^^0';^ 010 (ipilimumab), WUHPHOLPXPDE^^DQWL^&'^^^DQWLERGLHV^^DQWL^&7/$^^DGQHFWLQV^^DQWL^ CTLA4 domain antibodies, single chain DQWL^&7/$^^IUDJPHQWV^^KHDY\^FKDLQ^DQWL^&7/$^^ IUDJPHQWV^^OLJKW^FKDLQ^DQWL^&7/$^^IUDJPHQWV^^LQKLELWRUV^RI CTLA4 that DJRQL]H^WKH^FR^^ stimulatory pathway, the antibodies disclosed in PCT Publication No. WO 2001/014424, the antibodies disclosed in PCT Publication No. WO 2004/035607, the antibodies disclosed in U.S. Publication No. 2005/0201994, and the antibodies disclosed in granted European 3DWHQW^1R^^(3^^^^^^^^^%O^^$GGLWLRQDO^&7/$^^^DQWLERGLHV^DUH^GHVFULEHG^LQ^8^6^^ Pat. Nos. 5,811,097, 5,855,887, 6,051,227, and 6,984,720; in PCT Publication Nos. WO 01/14424 and WO 00/37504; and in U.S. Publication Nos. 2002/0039581 and 2^^^^^^^^^^^^2WKHU^DQWL^&7/$^^^DQWLERGLHV^WKDW^FDQ^EH^XVHG^LQ a method of the present Attorney Docket No.103361-086WO1 invention include, for example, those disclosed in: WO 98/42752; U.S. Pat. Nos. ^^^^^^^^^^DQG^^^^^^^^^^^^+XUZLW]^HW^DO^^^3URF^^1DWO^^$FDG^^6FL^^86$^^^^^^^^^^^^^^^^^^^^^ (1998); Camacho et al., J. Clin. Oncology, 22(145): Abstract No. 2505 (2004) (antibody &3^^^^^^^^^^0RN\U^HW^DO^^ &DQFHU^5HV^^^^^^^^^^^^^^^^^^^^^^^^DQG^8^6^^3DW^^1RV^^ 5,977,318, 6,682,736, 7,109,003, and 7,132,281. $GGLWLRQDO^DQWL^&7/$^^DQWDJRQLVWV^ include, but are not limited to, the following: any inhibitor that is capable of disrupting the ability of CD28 antigen to bind to its cognate ligand, to inhibit the ability of CTLA4 to ELQG^WR^LWV^FRJQDWH^OLJDQG^^WR^DXJPHQW^7^FHOO^UHVSRQVHV^YLD^WKH^FR^VWLPXODWRU\^SDthway, to disrupt the ability of B7 to bind to CD28 and/or CTLA4, to disrupt the ability of B7 to activate the costimulatory pathway, to disrupt the ability of CD80 to bind to CD28 and/or CTLA4, to disrupt the ability RI^&'^^^WR^DFWLYDWH^WKH^FR^VWLPXODWRU\ pathway, to disrupt the ability of CD86 to bind to CD28 and/or CTLA4, to disrupt the ability of CD86 to DFWLYDWH^WKH^FR^^VWLPXODWRU\^SDWKZD\^^DQG^WR^GLVUXSW^WKH^FRVWLPXODWRU\ pathway, in general from being activated. This necessarily includes small molecule inhibitors of CD28, CD80, &'^^^^&7/$^^^DPRQJ^RWKHU^PHPEHUV^RI^WKH^FR^VWLPXODWRU\^SDWKZD\^^DQWLERGLHV^GLUHFWHG WR^&'^^^^&'^^^^&'^^^^&7/$^^^DPRQJ^RWKHU^PHPEHUV^RI^WKH^FR^VWLPXODWRU\^SDWKZD\^^ antisense molecules directed against CD28, CD80, CD86, CTLA4, among other members RI^WKH^FR^^VWLPXODWRU\ pathway; adnectins directed against CD28, CD80, CD86, CTLA4, among other members of the costimulatory pathway, RNAi inhibitors (both single and double stranded) of CD28, CD80, CD86, CTLA4, among other members of the FR^ VWLPXODWRU\^SDWKZD\^^DPRQJ^RWKHU^DQWL^&7/$^^DQWDJRQLVWV^ In some embodiments, the small molecule USP30 inhibitors and chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy of the present disclosure may be used in combination with one or more therapeutic agents that LQKLELW^7,0^^^^%ORFNLQJ^WKH^ DFWLYDWLRQ^RI^7,0^^^E\^D^OLJDQG^^UHVXOWV^LQ^DQ^LQFUHDVH^LQ^7K^^FHOO^DFWLYDWLRQ^ Furthermore, 7,0^^^KDV^EHHQ^LGHQWLILHG^DV^DQ^LPSRUWDQW^LQKLELWRU\^UHFHSWRU^H[SUHVVHG^E\^H[KDXVWHG &'^^^7^FHOOV^^7,0^^^KDV^also been reported as a key regulator of nucleic acid mediated antitumor LPPXQLW\^^,Q^RQH^H[DPSOH^^7,0^^^KDV^EHHQ^VKRZQ^WR^EH^XSUHJXODWHG^RQ^WXPRU^ associated dendritic cells (TADCs). In some circumstances, a more efficacious result can be achieved by administering the small molecule USP30 inhibitor concurrently with a chemotherapeutic and/or cytotoxic agents inducing cardiomyopathy. Thus, in some aspects, the small molecule USP30 inhibitor can be administered to the subject at the same time, within 30 minutes, Attorney Docket No.103361-086WO1 within 1 hour, within 8 hours, within 12 hours, within 24 hours, within 48 hours, within 72 hours, or within 1 week. It is understood and herein contemplated that a single dose of a USP30 inhibitor alone may not be sufficient to achieve the desired result of treating, ameliorating and/or preventing cardiomyopathy. Methods of Administration The USP30 inhibitors as used in the methods described herein can be administered by any suitable method and technique presently or prospectively known to those skilled in the art. For example, the active components described herein can be formulated in a physiologically- or pharmaceutically-acceptable form and administered by any suitable route known in the art including, for example, oral and parenteral routes of administering. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection. Administration of the active components of their compositions can be a single administration, or at continuous and distinct intervals as can be readily determined by a person skilled in the art. Compositions, as described herein, comprising an active compound and an excipient of some sort may be useful in a variety of medical and non-medical applications. “Excipients” include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. General considerations in formulation and/or manufacture can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005). Exemplary excipients include, but are not limited to, any non-toxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as excipients include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters Attorney Docket No.103361-086WO1 such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. As would be appreciated by one of skill in this art, the excipients may be chosen based on what the composition is useful for. For example, with a pharmaceutical composition or cosmetic composition, the choice of the excipient will depend on the route of administration, the agent being delivered, time course of delivery of the agent, etc., and can be administered to humans and/or to animals, orally, rectally, parenterally, intracisternally, intravaginally, intranasally, intraperitoneally, topically (as by powders, creams, ointments, or drops), buccally, or as an oral or nasal spray. In some embodiments, the active compounds disclosed herein are administered topically. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof. Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof. Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays Attorney Docket No.103361-086WO1 (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl- pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof. Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and/or combinations thereof. Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, Attorney Docket No.103361-086WO1 potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent. Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium Attorney Docket No.103361-086WO1 phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer's solution, ethyl alcohol, etc., and combinations thereof. Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof. Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof. Additionally, the composition may further comprise a polymer. Exemplary polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethyl cellulose (CMC) and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts, carboxymethylhydroxyethylcellulose (CMHEC) and its various salts, other polysaccharides and polysaccharide derivatives such as starch, dextran, dextran Attorney Docket No.103361-086WO1 derivatives, chitosan, and alginic acid and its various salts, carageenan, various gums, including xanthan gum, guar gum, gum arabic, gum karaya, gum ghatti, konjac and gum tragacanth, glycosaminoglycans and proteoglycans such as hyaluronic acid and its salts, proteins such as gelatin, collagen, albumin, and fibrin, other polymers, for example, polyhydroxyacids such as polylactide, polyglycolide, polyl(lactide-co-glycolide) and poly(.epsilon.-caprolactone-co-glycolide)-, carboxyvinyl polymers and their salts (e.g., carbomer), polyvinylpyrrolidone (PVP), polyacrylic acid and its salts, polyacrylamide, polyacrylic acid/acrylamide copolymer, polyalkylene oxides such as polyethylene oxide, polypropylene oxide, poly(ethylene oxide- propylene oxide), and a Pluronic polymer, polyoxy ethylene (polyethylene glycol), polyanhydrides, polyvinylalchol, polyethyleneamine and polypyrridine, polyethylene glycol (PEG) polymers, such as PEGylated lipids (e.g., PEG-stearate, l,2-Distearoyl-sn-glycero-3-Phosphoethanolamine- N-[Methoxy(Polyethylene glycol)-1000], 1,2-Distearoyl-sn-glycero-3- Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-2000], and 1,2-Distearoyl-sn- glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-5000]), copolymers and salts thereof. Additionally, the composition may further comprise an emulsifying agent. Exemplary emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N-vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non- cationic polyacrylates, such as poly (meth) acrylic acid, and esters amide and hydroxy alkyl amides thereof, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene Attorney Docket No.103361-086WO1 sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof. In certain embodiments, the emulsifying agent is cholesterol. Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid composition may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable compositions, for example, injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be an injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In certain embodiments, the particles are suspended in a carrier fluid comprising 1% (w/v) sodium carboxymethyl cellulose and 0.1% (v/v) Tween 80. The injectable composition can be sterilized, for Attorney Docket No.103361-086WO1 example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles. Solid compositions include capsules, tablets, pills, powders, and granules. In such solid compositions, the particles are mixed with at least one excipient and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active Attorney Docket No.103361-086WO1 compound is admixed with an excipient and any needed preservatives or buffers as may be required. The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the nanoparticles in a proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the particles in a polymer matrix or gel. The active ingredient may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result. The exact amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular active ingredient, its mode of administration, its mode of activity, and the like. The active ingredient, whether the active compound itself, or the active compound in combination with an agent, is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the active ingredient will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. Attorney Docket No.103361-086WO1 The active ingredient may be administered by any route. In some embodiments, the active ingredient is administered via a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the active ingredient (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc. The exact amount of an active ingredient required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art. The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms or disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross- reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. In some embodiments, the composition as used in the methods described herein may be administered in combination or alternation with one or more additional active agents. Representative examples additional active agents include anti-inflammatory Attorney Docket No.103361-086WO1 agents (including steroids and non-steroidal anti-inflammatory agents), anti-coagulant agents, antiplatelet agents, and antiseptic agents. Representative examples of steroidal anti-inflammatory agents include, but are not limited to, hydrocortisone, dexamethasone, prednisolone, prednisone, triamcinolone, methylprednisolone, budesonide, betamethasone, cortisone, and deflazacort. Representative examples of non-steroidal anti-inflammatory drugs include ibuprofen, naproxen, ketoprofen, tolmetin, etodolac, fenoprofen, flurbiprofen, diclofenac, piroxicam, indomethacin, sulindax, meloxicam, nabumetone, oxaprozin, mefenamic acid, and diflunisal. A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. By way of non-limiting illustration, examples of certain embodiments of the present disclosure are given below. EXAMPLES The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in qC or is at ambient temperature, and pressure is at or near atmospheric. Example 1: Pharmacological Inhibition of USP30 activates Tissue-specific Mitophagy Summary Aim: Mitophagy is the regulated process that targets damaged or dysfunctional mitochondria for lysosomal-mediated removal. This process is an essential element of mitochondrial quality control, and dysregulation of mitophagy may contribute to a host of diseases, most notably neurodegenerative conditions such as Parkinson’s disease. Mitochondria targeted for mitophagic destruction are molecularly marked by the Attorney Docket No.103361-086WO1 ubiquitination of several outer mitochondrial membrane (OMM) proteins. This ubiquitination is positively regulated, in part, by the mitochondrial-targeted kinase PINK1 and the E3 ubiquitin ligase Parkin. In contrast, the reverse phenomenon, deubiquitination, removes ubiquitin from Parkin substrates embedded in the OMM proteins, antagonizing mitophagy. Recent evidence suggests that the mitochondrial deubiquitinase USP30 negatively regulates Parkin mediated mitophagy, providing opportunities to identify USP30 inhibitors and test for their effects in augmenting mitophagy. Here we will characterize a USP30 inhibitor and demonstrate how the pharmacological inhibition of USP30 can augment stress-induced mitophagic flux. Methods: We have conducted mitophagy and mitochondrial analyses in cultured cells. We have determined the plasma pharmacokinetics of the USP30 inhibitor in mice and conducted analyses using the mt-Keima mice to measure in vivo mitophagy directly. Results: The compound has minimal mitochondrial toxicity in cultured cells and is tolerated well in mice. Interestingly, we demonstrated tissue-specific induction of mitophagy following USP30 pharmacological inhibition. In particular, pharmacological inhibition of USP30 induces a significant increase in cardiac mitophagy without detriment to cardiac function. Conclusion: These findings support the evidence that USP30 inhibition may serve as a specific strategy to selectively increase mitophagic flux, allowing for the development of novel therapeutic approaches. Background Mitophagy is emerging as a critical regulator of mitochondrial homeostasis at both the cellular and organismal level. Mitophagy declines with age and, dysregulation of mitophagy is associated with a wide range of age-related human diseases, most notably neurodegenerative conditions such as Parkinson’s disease (PD). The understanding of the mechanisms that govern mitophagy and regulate the removal of mitochondria upon mitochondrial damage has advanced vastly. Evidence suggests that mitophagy requires the post-translational tagging of multiple outer mitochondrial membrane proteins (OMM) with ubiquitin to signal and recruit the autophagosomal machinery. The E3-ubiquitin ligase, Parkin, has been implicated as a critical enzyme that catalyzes the ubiquitination of a wide range of mitochondrial proteins. Parkin’s recruitment to the mitochondria involves the PTEN-induced putative kinase 1 (PINK1), a mitochondrial-targeted kinase whose Attorney Docket No.103361-086WO1 stability is regulated, at least in part, by mitochondrial membrane potential, suggesting that PINK1 and Parkin function in the same biochemical pathway. Loss-of-function mutations in PINK1 or Parkin also have been identified as a cause for familial, early-onset Parkinson disease, strengthening the premise that these two proteins are critical for optimal mitochondrial quality control. The use of innovative mouse models and patient-derived induced pluripotent stem cells (iPSCs) has dramatically enhanced our ability to further explore the clinical relevance of mitophagy and create therapies where mitophagy modulation may prove beneficial. Much remains to be understood regarding the additional inputs into the PINK1- Parkin’s regulatory hub, catalyzing the forward reaction to ubiquitinate a range of OMM proteins and controlling mitophagy. As yet, relatively little is known regarding the reverse phenomenon’s role, i.e., deubiquitination, during mitophagy activation, and how these effectors contribute to mitophagy regulation. Deubiquitination is thought to be carried out enzymatically by a large family of proteins termed deubiquitinating enzymes or DUBs. Mitochondria have at least three DUBs, including the Ub-specific protease 8 (USP8), USP15, and USP30, which together appear to antagonize Parkin’s ability to regulate mitophagic flux. Of these, perhaps the most convincing physiological evidence linking DUBs to mitophagy has come from the study of USP30. USP30 is a deubiquitylase constitutively associated with the OMM. Recent advances have demonstrated that USP30 can counteract 3DUNLQ^GHSHQGHQW^PLWRSKDJ\^E\^GHXELTXLW\ODWLQJ^200^SURWHLQV^^LQFOXGLQJ^ TOMM20. In addition, genetic manipulations of USP30 have begun to elucidate how this enzyme contributes to the process of mitophagy. In cultured cells, including neurons, USP30 overexpression inhibits mitophagy, and this effect is not seen when a catalytically inactive mutant of USP30 is employed. Furthermore, the knockdown of USP30 enhances mitophagy in cultured cells. Interestingly, knockdown of USP30 can rescue the defect in mitophagy seen in Parkin or PINK1-deficient flies. These, and subsequent observations, have suggested that inhibiting USP30 might provide a specific strategy to increase mitophagic flux selectively. Identifying specific small-molecule inhibitors of USP30 will offer valuable opportunities to dissect the role of mitophagy pharmacologically in health and disease. Recent efforts have generated a few USP30 inhibitors, exemplified by some N- cyano pyrrolidines and a racemic phenylalanine derivative, to lower the threshold for mitophagy induction and stimulate stress induced mitophagy. However, much of the Attorney Docket No.103361-086WO1 current data rely on cells engineered to overexpress Parkin. Much less understood are the inhibitors of USP30 and whether inhibiting USP30 will activate mitophagy in vivo. Assessing the role of USP30 inhibition in mice may further enable the clinical development of USP30 inhibitors in a wide range of age-related human diseases. Materials and methods Cell culture and reagents HeLa cells and mouse embryonic fibroblasts (MEFs) were grown in Dulbecco's minimum essential medium (DMEM) with 10% fetal bovine serum (FBS) supplemented with penicillin-streptomycin. HeLa Parkin, PINK1 KO cells, WT and MFN2 KO cells were previously described. Cells stably expressing USP30 were generated using lentiviral vectors of pLVX-Puro-Myc-USP30. The USP30 plasmid was obtained from Addgene. The plasmid was transferred into a lentiviral vector and viral particles were prepared by transiently transfecting HEK293T using standard methods. For the drug treatment experiments, cells were incubated in medium containing a mixture of 5 μM oligomycin and 5 μM antimycin A (A/O; see figures for treatment times). In 18 h treatment, A/O were used in combination with 10 μM quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]- methyl ketone (QVD), a broad-spectrum caspase inhibitor. ST51000539 (ST-539) was purchased from TimTec, Inc. Other chemicals were from Sigma-Aldrich (St. Louis, MO, USA). For FACS analysis, cells stably expressing mt-Keima were incubated in medium containing a mixture of 1 μM oligomycin and 1 μM antimycin A for 1.5 h. Prior to A/O treatment, cultures were treated with DMSO or ST-539 at 3μg/ml. Cells were trypsinized, washed once with PBS buffer and then resXVSHQGHG^LQWR^^^^^^O^RI^3%6^SULRU^WR^DQDO\VLV^ using a BD Fortessa flow cytometer as previously described. Western blotting Cells were lysed in RIPA buffer (50 mM Tris-HCl, at pH 8.0; 150 mM NaCl; 1% (vol/vol) Nonidet P-40; 0.5% sodium deoxycholate, 0.1% SDS and protease inhibitor cocktail (Roche)) on ice. Primary antibodies were used at the following concentrations: USP30 (Santa Cruz, sc-515235, 1:200); TOM20 (Cell Signaling Technology, 42406S, 1:1000); TOM40 (Proteintech, 18409-1-AP, 1:1000); NDP52 (Cell Signaling Technology, 60732S, 1:1000); TIM23 (Proteintech, 11123-1-AP, 1:500); LC3A/B (Cell Signaling Technology, 4108S, 1:1000); GAPDH (Cell Signaling Technology, 5175S, 1:1000); PINK1 (Cell Signaling Technology, 6946S, 1:1000); ACTIN (Cell Signaling Technology, 3700S, 1:1000). The membranes were incubated with anti-rabbit (LI-COR, 926-32211, Attorney Docket No.103361-086WO1 1:15000) or anti-mouse (LI-COR, 926-68072, 1:15000) IgG secondary antibodies for 1 h at room temperature. Images were captured using the Odyssey system (LI-Cor). One representative blot is shown of three independent experiments. Seahorse assay Measurement of intact cellular respiration was performed using the Seahorse XFe96 Analyzer as previously described. In brief, 2 x 104 cells per well were seeded in the Seahorse XF Cell Culture Microplate (Agilent) using high-glucose DMEM at 37°C, with a humidified atmosphere of 5% CO2, overnight. And a sensor cartridge was hydrated in Seahorse XF Calibrant in a non-CO2 incubator overnight at 37 °C. The high-glucose DMEM in Cell Culture Microplate was changed to warmed assay medium and placed into a 37 °C non-CO2 incubator for 45 minutes prior to the assay. Oligomycin (1.5μM/well), FCCP (1μM/well) and Antimycin A (0.5μM/well) were supplemented at 18 minutes, 36 minutes and 54 minutes, respectively. The results were analyzed using the Seahorse Wave software. 0HDVXUHPHQW^RI^ǻȌP ǻȌP^ZDV^PHDVXUHG^XVLQJ^D^IOXRUHVFHQFH^PLFURSODWH^UHDGHU^^%LR7HN^,QVWUXPHQWV^^ in cells preincubated with Tetramethylrhodamine methyl ester (TMRM, Thermo Scientific) following manufacturer's instructions. Cells were washed in PBS before resuspension in Hank’s balanced salt solution (HBSS; 156 mM NaCl, 3 mM KCl, 2 mM MgSO4, 1.25 mM KH2PO4, 2 mM CaCl2, 10 mM glucose and 10 mM HEPES; pH adjusted to 7.35 with NaOH) (1.0×106 cells/ml) containing 50 nM TMRM. For each individual experiment, average TMRM fluorescence was normalized to control cells. Confocal Microscopy Fluorescent samples were examined with a Zeiss LSM 780 confocal microscope (Carl Zeiss MicroImaging). As previously described2, fluorescence of mt-Keima was imaged in two channels via two sequential excitations (458 nm, green; 561 nm, red) and using a 570- to 695-nm emission range. Confocal experiments for parkin translocation were performed using a HeLa cell line stably expressing YFP-Parkin plated on 35mm coverglass #1.5 chamber dishes (MatTek). These cells were treated for 2 h with DMSO as vehicle control or with A/O. YFP was imaged with a 514-nm excitation and 520- to 570- emission filters. Representative confocal images were processed using Imaris software by contrast linear stretch only. Calculation of mitophagy based on mt-Keima signal was performed using Zeiss ZEN software as previously described2. The average of four images Attorney Docket No.103361-086WO1 from each tissue sample was taken, and the values were normalized to the average value seen in the controls, assigned the value of one. Animals The mt-Keima mouse . ST-539 was dissolved into 1% DMSO in Sesame oil and injected intraperitoneally (i.p.) at doses of 25 mg/kg/day with five total doses. Both male and female mice were used in this study. The control group received vehicle only. Echocardiographic measurements were taken using a Vevo3100 Visual Sonics (Visual Sonics) system. The mice were lightly anesthetized with isoflurane and the ejection fraction, fractional shortening, and ventricular chamber dimensions were determined using 2-D-guided M mode images. Ejection fraction, fractional shortening, ventricular chamber dimensions, and left ventricular mass were calculated automatically using the VevoLAB program. All experiments involving animals were approved by the Institutional Animal Care and Use Committee at The Ohio State University. Pharmacokinetics ST-539 was dissolved into 1% DMSO in Sesame oil and injected intraperitoneally (i.p.) at doses of 25 mg/kg. Serial blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4 and 8 hours post dosing. Mice were euthanized at 24 hours post dosing. A terminal blood sample was collected by cardiac puncture followed by harvesting the brain and heart. Transcardial perfusion was performed prior to brain collection. The blood samples were placed in microtubes pretreated with K2EDTA as an anticoagulant and kept on ice until centrifugation. The tissue samples were rinsed using cold distilled water to remove blood, blotted dry, weighed and stored on dry ice until LC/MS/MS analysis. Plasma was transferred into polypropylene tubes or 96-well plates, quick frozen on dry ice, and stored at - 70 ± 10°C until LC/MS/MS analysis. Statistics Statistical analysis was performed with an unpaired 2-WDLOHG^W^WHVW^^3^YDOXHV^^^^^^^ were considered significant. Results are presented as the mean ± SD. Results ST-539 inhibits USP30 and promotes mitophagy The enzymatic activity of Parkin is to function as an E3 ubiquitin ligase. Evidence suggests that Parkin can ubiquitinate a wide range of OMM proteins, including the translocase of outer membrane 20 (TOM20). To investigate TOM20 ubiquitination during mitophagy, we treated HeLa cells stably expressing YFP-Parkin (Hela-Parkin) for up to 18 Attorney Docket No.103361-086WO1 h with both the mitochondrial complex III inhibitor antimycin A and the ATP synthase inhibitor oligomycin (antimycin A/oligomycin/ [A/O]; Figure 1A). We observed that in HeLa cells engineered to express Parkin, the addition of a cocktail of mitochondrial inhibitors triggered ubiquitination of TOM20, and the subsequent fall in TOM20 protein levels (Figure 1A). A/O treatment also results in a decline in the abundance of the OMM protein TOM40 and the inner mitochondrial protein TIM23 (Figure 1A). Previous results from cell culture experiments and flies suggest that USP30 can deubiquitylate OMM proteins and antagonize Parkin’s activity. In this context, increased expression of USP30 blocked the accumulation of ubiquitinated TOM20 and prevented the destruction of this outer mitochondrial protein, as well as TOM40 and TIM23, after A/O treatment (Figure 1A). We then employed this cellular assay to monitor TOM20 turnover, and analyzed compounds known to be associated with the ubiquitination process for inhibitors of USP30. From our screen, the most potent mitophagy inducer was ST-539, a racemic phenylalanine derivative (Figure 1B). This compound and similar structures selectively inhibit USP30 enzyme function in vitro. We defined the effects of this chemical using biochemical assays. With ST-^^^^DW^^^^^J^PO, we found A/O treatment caused a ubiquitinated TOM20 and a loss of TOM20 protein level by ~90% (Figure 1C), confirming inhibited degradation of TOM20 in the presence of USP30. A close correlation exists between the TOM20 ubiquitination and the ST-539 dosage (Figure 1C). Initially to assess mitophagy in cells, we monitored the degradation of the inner membrane protein, the translocase of the inner membrane 23 (TIM23), by immunoblotting (Figure 5A). Following 18h-A/O treatment, immunoblotting showed the protein levels of TIM23 and TOM40 decreased significantly in Hela-Parkin cells (Figures 5A-5B). USP30's overexpression prevented a reduction in TIM23 and TOM40 levels. Moreover, ST-539 restored TIM23 and TOM40 degradation indicating ST-539 could promote mitophagy via USP30 inhibition (Figures 5A-5B). We employed a sensitive fluorescence-activated cell sorting (FACS)-based method for detecting mitophagy using the pH-dependent fluorescent protein Keima. Keima is a pH-sensitive, dual-excitation ratiometric fluorescent protein that can be targeted to the mitochondrial matrix utilizing the mitochondria-targeting sequence from COX VIII, allowing for the detection of mitophagy (mt-Keima). When mt-Keima is present in the physiological pH of the mitochondria (pH 8.0), the shorter-wavelength excitation predominates; mt-Keima undergoes a shift to longer-wavelength excitation in acidic Attorney Docket No.103361-086WO1 conditions, such as in autolysosomes (pH 4.5). We exploited the mt-Keima probe and measured mitophagy in HeLa-Parkin cells and HeLa-Parkin cells that express USP30. Only ~1% of HeLa-Parkin cells display mitophagy under basal conditions. Consistent with previous observations, we confirmed that A/O induced a rapid and marked increase in overall red mt-Keima fluorescence, consistent with increased mitophagy (Figure 1D). HeLa-Parkin cells expressing USP30 showed minimal increase in mitophagy after A/O treatment. Interestingly, ST-539 treatment restored A/O induced mitophagy in HeLa- Parkin cells expressing USP30 (Figure 1D). PINK1 and Parkin are required for ST-539 induced ubiquitination Genetic suppression RI^863^^^LQ^3DUNLQ^RYHUH[SUHVVLQJ^FHOOV^SURPRWHV^WKH^ clearance of mitochondria in response to mitochondrial depolarizing agents. Recent evidence suggests endogenous Parkin expression is sufficient to initiate GHSRODUL]DWLRQ^ induced mitophagy. To investigate if the PINK1/Parkin pathway is required for ST-539 induced mitophagy, we analyzed TOM20 ubiquitination in wild-type (WT) HeLa cells, which express little to no endogenous Parkin, as well as in WT and PINK1 knockout (KO) HeLa cells stably expressing YFP-tagged Parkin. In PINK1 KO cells, A/O induced Parkin mitochondrial translocation and mitophagy flux was inhibited (Figure 2A and Figure 6). Moreover, the loss of PINK1 was sufficient to prevent A/O induced TOM20 ubiquitination and mitophagy (Figure 2B). Under the baseline, all three cell lines exhibited a similar degree of TOM20 ubiquitination and protein level (Figure 2B). However, A/O induced TOM20 ubiquitination and a decline in the TOM20 level only in cells expressing both ectopic Parkin and endogenous PINK1 (Figure 2B), which was further potentiated by the addition of ST-539 (Figure 2B). Long term treatment (18 h) of ST-539 did not promote TOM20 ubiquitination independent of the functional PINK1/Parkin pathway (Figure 2C). A more significant reduction in NDP52, a mitophagy receptor that signals autophagosome assembly proximal to the individual damaged mitochondria, and mitochondrial protein TOM20 levels occurred in the presence of ST-539 in Parkin positive cells relative to the vehicle treated cells upon A/O, but not in WT Hela or PINK1 KO cells (Figure 2C). These results demonstrate that following A/O, although ST-539 promoted ubiquitination and mitophagy occurs, PINK1/Parkin activity is necessary for ST-539’s activity. Effects of USP30 inhibition on mitochondrial function We next investigated if the pharmacological inhibition of USP30 by ST-539 could influence mitochondrial functions. We initially analyzed mitochondrial function using Attorney Docket No.103361-086WO1 Tetramethylrhodamine (TMRM), a dye requiring mitochondrial membrane potential to accumulate within the mitochondria. ST-539 treatment with concentrations of 3 to 10 ^J^PO^GLG^QRW^EORFN^7050^VWDLQLQJ^^ZKLFK^LV^LQ^FRQWUDVW^WR^WKH^VLJQLILFDQW^ORVV^RI^VWDLQLQJ^ when using Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) treatment (Figure 3A). The result indicates that ST-539 may not disrupt mitochondrial membrane potential. Next, we measured oxygen consumption using the Seahorse assay following ^^ௗK^RI^67-539 treatment. Interestingly, we detected a slight increase in basal and maximal respiration in Hela-Parkin and Hela-Parkin cells expressing USP30 following ST-539 treatment at high dose (Figure 3B). Cell proliferation was maintained after ST-539 WUHDWPHQW^IRU^^^ௗKRXUV^^3UHYLRXV^VWXGLHV^UHvealed that USP30 participates in maintaining mitochondrial morphology. To investigate ST-539’s role in potential regulation of the mitochondrial dynamic processes, we treated Mfn2-knockout (Mfn2í^í) MEF cells containing a fragmented mitochondrial network characterized by short, rod-shaped PLWRFKRQGULD^^+RZHYHU^^WKH^DGGLWLRQ^RI^^^RU^^^^^J^^PO^67-539 did not induce the elongation of mitochondria significantly (Figure 3C). Similarly, ST-539 failed to change the mitochondrial morphology in the wild type MEFs (Figure 3C). Together the data imply that the pharmacological inhibition of USP30 by ST-539 marginally alters mitochondrial function, regardless of USP30 expression. ST-539 induced tissue specific mitophagy in vivo. The correlation between USP30 and early-onset Parkinson’s disease (PD) associated PINK1 and Parkin pathway creates increased attention to this enzyme. A set of USP30 inhibitors have been identified with specific USP30 binding activity in vitro. Nonetheless, it remains unclear whether USP30 inhibition could regulate mitophagy in vivo. We initially attempted to define the plasma pharmacokinetic properties of ST-539 in mice. We administered the dose of 25 mg/kg ST-539 intraperitoneally (i.p). Figure 4A illustrates the post-administration plasma concentration-time curves. The maximum plasma concentration (Cmax) following the i.p. administration of ST-539 in mice was about ^^^^J^PO^^7KH^KDOI-life (T1/2) of ST-539 is about 3.85 hr., with a time to reach peak plasma concentration (Tmax) value of 1.33 hr. (Table 1). We calculated the area under the plasma drug concentration-time curve (AUC), to reflect the extent of drug exposure, and obtained D^YDOXH^RI^a^^^^^J^K^PO^^7DEOH^^^^^7KHVH^ILQGLQJV^VXJJHVW^WKDW^administrating daily i.p. doses of 25mg/kg could be used to test whether of ST-539 could activate mitophagy in vivo. Attorney Docket No.103361-086WO1 Table 1. Pharmacokinetic parameters of the plasma ST-539 concentration-time curve. Cmax: maximum plasma concentration; Tmax: time to reach Cmax; T1/2: half-life; AUClast: area under the curve from t=0 to the time of the last quantifiable concentration; AUCinf: AUC from t=0 to infinity; MRTinf: mean residence time. We sought to provide the first direct measurements of mitophagy following ST- 539 treatment, employing the pH-sensitive fluorescent protein mt-Keima, which can provide rapid and faithful determination of mitophagy in a mouse model. The mt-Keima mice received daily injections of ST-539 or a vehicle for five days. We visualized the basal mitophagic levels via tissues obtained from mt-Keima mice, which presented as red and green punctate within the cardiac and hepatic sections (Figure 4B). Treating mt-Keima mice with ST-539 resulted in a marked induction of the red signal in the heart tissue (Figure 4B), suggesting an augmented cardiac mitophagy. Consistent with these observations, the hearts following ST-539 treatment demonstrated an increase in LC3- II/LC3-I ratio compared to control hearts (Figure 7A). To verify that the mitophagy activation was not associated with cardiac pathology, we performed an echocardiographic analysis in the treated mice to monitor cardiac morphology and function following ST-539 treatment. We observed minimal differences in left ventricle systolic function represented by the ejection fraction (EF) (Figure 4C). Moreover, ST-539 treatment does not appear to impact cardiac output or left ventricular posterior wall thickness (LVPWs) (Figure 4C). The results suggest that pharmacologically manipulating USP30 activity can stimulate mitophagy in the heart independent of cardiac pathological responses. However, mitophagic flux in metabolically different organs such as the liver (Figure 4B and Figure Attorney Docket No.103361-086WO1 7B) or the hippocampus of the brain remains unchanged following the ST-539 administration. As such, the current dosage of ST-539 appears to be safe in mice, and ST- 539 represents a potential USP30 inhibitor to regulate in vivo mitophagy in a tissue specific manner. This may reflect variation in USP30 expression levels among tissues, although we cannot exclude the possibility that the lack of mitophagy activation in the brain tissue is due to insufficient exposure to ST-539. Overall, our results demonstrate the pharmacological inhibition of USP30 by ST- 539 modulates PINK1/Parkin dependent mitophagy, and efficiently induces cardiac mitophagy. Further investigation of ST-539, to determine its detailed Pharmacokinetic- Pharmacodynamic (PKPD) hopefully leads to potential therapies for multiple diseases. Discussion Maintaining mitochondrial quality through mitophagy to selectively eliminate dysfunctional mitochondria could be particularly crucial under disease conditions. Multiple pathophysiological processes have been implicated in the regulation of mitophagy, and the mitophagic removal may require exquisite regulatory controls. For instance, if the removal is too exuberant, the energetically demanding tissues such as the heart and brain, may become maladapted to its environment. The complexity of mitophagy regulation has impeded identification of a rate-limiting therapeutic target. The benign effects of USP30 inhibition may afford a means to enhance suitable mitophagy, making it a promising target candidate. Our study, both in vitro and in a mouse model, reports that ST-539 inhibits USP30, effectively activating mitophagy in cells and in the heart. Future research will explore the use of this compound and its derivatives in disease models, such as myocardial infarction and age-related heart failure, both of which implicate mitophagy dysregulation. It is well established that the USP30 dependent suppression of mitophagy may rely on over-expressed Parkin together with an overt depolarization. Nevertheless, deletion of USP30 from cells with endogenous Parkin only results in a modest effect on mitophagic flux, and Parkin can rapidly overcome USP30’s activity to allow maximal activation of the Parkin dependent mitophagy. Moreover, the ubiquitylation of the majority of Parkin targets is unaffected upon USP30 deletion. Further studies are required to understand the role of USP30 in buffering Parkin activation and mitophagy regulation. Interestingly, recent studies have provided a comprehensive analysis of the impact of USP30 on Attorney Docket No.103361-086WO1 mitochondrial ubiquitylation dynamics, establishing a model proposing that USP30 loss or inhibition may boost mitophagy by lowering the threshold of mitochondrial damage. The inability of ST-539 to induce hepatic mitophagy is somewhat unexpected. We hypothesize that this reflects the differences of basal mitophagy threshold in hepatocytes compared to cardiomyocytes following USP30 inhibition. This result is consistent with previous work comparing the basal levels of mitophagy in various mouse tissues, where we observed tissue-specific differences in mitophagy, with relatively high mitophagic rates seen in organs such as the heart. Our cellular studies reveal a minimal change in mitophagy following ST-539 treatment in the absence of mitochondrial stress. As hepatic mitophagy is sensitive to environmental and genetic perturbations, it is possible that ST- 539 may stimulate mitophagy in the liver when animals are exposed to specific stressors. Moreover, the liver and the brain exhibit a higher level of USP30 expression than cardiac muscle. An increased dose and/or the duration of ST-539 administration may be required to effectively induce mitophagy in the liver or brain. Of note, we have detected ST-539 in modest concentrations from the mouse brain homogenate, suggesting a potential brain distribution of ST-539 (Table 2). Though untested, mitophagy induction following USP30 inhibition may differ substantially among tissues and vary widely between cell types in the same tissue. Table 2. Tissue concentrations of ST-53924 Hours Post-dose in Male C57BL/6 Mice (ng/g). Based on our studies, ST539 emerges as a promising compound for the in vivo evaluation of USP30 inhibition. However, it is not clear what dose or duration of ST539 is required to see the beneficial effects of mitophagy induction in diseased models. Therefore, altering the dose and the duration of ST-539 administration could modulate the tissue-specific effects of USP30 inhibition. A successful result would prompt additional tests of the compound’s specificity and any off-target effects in vivo. Additionally, the PK/PD and toxicity profiles of ST-539 should allow further preclinical assessment of Attorney Docket No.103361-086WO1 USP30 inhibition as a therapeutic strategy for a wide variety of diseases. Encouragingly, the crystal structure of human USP30 bound to monoubiquitin and Lys6-linked di- ubiquitin was reported recently, providing insights into the activity and regulation of USP30 to facilitate drug design against this enzyme. References 1. McWilliams TG, Prescott AR, Montava-Garriga L, et al. Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand. Cell metabolism. 2018;27(2):439-449 e435. 2. Sun N, Yun J, Liu J, et al. Measuring In Vivo Mitophagy. Molecular cell. 2015;60(4):685-696. 3. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nature reviews Molecular cell biology. 2011;12(1):9-14. 4. Li H, Ham A, Ma TC, et al. Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations. Autophagy. 2019;15(1):113-130. 5. Sun N, Youle RJ, Finkel T. The Mitochondrial Basis of Aging. Mol Cell. 2016;61(5):654-666. 6. Pickles S, Vigie P, Youle RJ. Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance. Current biology : CB. 2018;28(4):R170-R185. 7. Fivenson EM, Lautrup S, Sun N, et al. Mitophagy in neurodegeneration and aging. Neurochem Int. 2017;109:202-209. 8. Levine B, Kroemer G. Biological Functions of Autophagy Genes: A Disease Perspective. Cell. 2019;176(1-2):11-42. 9. McWilliams TG, Muqit MM. PINK1 and Parkin: emerging themes in mitochondrial homeostasis. Curr Opin Cell Biol.2017;45:83-91. 10. Ordureau A, Paulo JA, Zhang W, et al. Dynamics of PARKIN-Dependent Mitochondrial Ubiquitylation in Induced Neurons and Model Systems Revealed by Digital Snapshot Proteomics. Mol Cell. 2018;70(2):211-227 e218. 11. Hasson SA, Kane LA, Yamano K, et al. High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature. 2013;504(7479):291-295. 12. Sarraf SA, Raman M, Guarani-Pereira V, et al. Landscape of the PARKIN- dependent ubiquitylome in response to mitochondrial depolarization. Nature. 2013;496(7445):372-376. Attorney Docket No.103361-086WO1 13. Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin-induced mitophagy in the pathogenesis of Parkinson disease. Autophagy. 2009;5(5):706-708. 14. Narendra DP, Jin SM, Tanaka A, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS biology. 2010;8(1):e1000298. 15. Clark IE, Dodson MW, Jiang C, et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. 2006;441(7097):1162-1166. 16. Narendra D, Walker JE, Youle R. Mitochondrial quality control mediated by PINK1 and Parkin: links to parkinsonism. Cold Spring Harb Perspect Biol. 2012;4(11). 17. Pan PY, Yue Z. Genetic causes of Parkinson's disease and their links to autophagy regulation. Parkinsonism Relat Disord. 2014;20 Suppl 1:S154-157. 18. Fang EF, Hou Y, Palikaras K, et al. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 2019;22(3):401-412. 19. Ordureau A, Paulo JA, Zhang J, et al. Global Landscape and Dynamics of Parkin and USP30-Dependent Ubiquitylomes in iNeurons during Mitophagic Signaling. Molecular cell. 2020;77(5):1124-1142 e1110. 20. McWilliams TG, Prescott AR, Allen GF, et al. mito-QC illuminates mitophagy and mitochondrial architecture in vivo. J Cell Biol. 2016;214(3):333-345. 21. Bingol B, Tea JS, Phu L, et al. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature. 2014;510(7505):370-375. 22. Cunningham CN, Baughman JM, Phu L, et al. USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria. Nature cell biology. 2015;17(2):160- 169. 23. Bingol B, Sheng M. Mechanisms of mitophagy: PINK1, Parkin, USP30 and beyond. Free Radic Biol Med. 2016;100:210-222. 24. Torre S, Polyak MJ, Langlais D, et al. USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation. Nat Immunol. 2017;18(1):54-63. 25. Durcan TM, Fon EA. The three 'P's of mitophagy: PARKIN, PINK1, and post- translational modifications. Genes Dev. 2015;29(10):989-999. 26. Durcan TM, Tang MY, Perusse JR, et al. USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin. EMBO J. 2014;33(21):2473-2491. Attorney Docket No.103361-086WO1 27. Liang JR, Martinez A, Lane JD, Mayor U, Clague MJ, Urbé S. USP30 deubiquitylates mitochondrial Parkin substrates and restricts apoptotic cell death. EMBO reports. 2015;16(5):618-627. 28. Gersch M, Gladkova C, Schubert AF, Michel MA, Maslen S, Komander D. Mechanism and regulation of the Lys6-selective deubiquitinase USP30. Nat Struct Mol Biol. 2017;24(11):920-930. 29. Rusilowicz-Jones EV, Jardine J, Kallinos A, et al. USP30 sets a trigger threshold for PINK1-PARKIN amplification of mitochondrial ubiquitylation. Life science alliance. 2020;3(8). 30. Kluge AF, Lagu BR, Maiti P, et al. Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy. Bioorganic & medicinal chemistry letters. 2018;28(15):2655-2659. 31. Lazarou M, Sliter DA, Kane LA, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015;524(7565):309-314. 32. Katayama H, Kogure T, Mizushima N, Yoshimori T, Miyawaki A. A sensitive and quantitative technique for detecting autophagic events based on lysosomal delivery. Chem Biol. 2011;18(8):1042-1052. 33. Denison SR, Wang F, Becker NA, et al. Alterations in the common fragile site gene Parkin in ovarian and other cancers. Oncogene. 2003;22(51):8370-8378. 34. Poot M, Zhang YZ, Kramer JA, et al. Analysis of mitochondrial morphology and function with novel fixable fluorescent stains. J Histochem Cytochem. 1996;44(12):1363- 1372. 35. Nakamura N, Hirose S. Regulation of mitochondrial morphology by USP30, a deubiquitinating enzyme present in the mitochondrial outer membrane. Mol Biol Cell. 2008;19(5):1903-1911. 36. Yue W, Chen Z, Liu H, et al. A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30. Cell Res.2014;24(4):482-496. 37. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003;160(2):189-200. 38. Sun N, Malide D, Liu J, Rovira, II, Combs CA, Finkel T. A fluorescence-based imaging method to measure in vitro and in vivo mitophagy using mt-Keima. Nat Protoc. 2017;12(8):1576-1587. Attorney Docket No.103361-086WO1 39. Uhlén M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome. Science (New York, NY). 2015;347(6220):1260419. 40. Fagerberg L, Hallström BM, Oksvold P, et al. Analysis of the Human Tissue- specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics. Molecular & cellular proteomics : MCP. 2014;13(2):397-406. 41. Zhang R, Krigman J, Luo H, Ozgen S, Yang M, Sun N. Mitophagy in cardiovascular homeostasis. Mech Ageing Dev. 2020;188:111245. 42. Killackey SA, Philpott DJ, Girardin SE. Mitophagy pathways in health and disease. J Cell Biol. 2020;219(11). 43. Sliter DA, Martinez J, Hao L, et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature. 2018;561(7722):258-262. 44. Palikaras K, Lionaki E, Tavernarakis N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nature cell biology.2018;20(9):1013-1022. 45. Bravo-San Pedro JM, Kroemer G, Galluzzi L. Autophagy and Mitophagy in Cardiovascular Disease. Circ Res. 2017;120(11):1812-1824. 46. Kubli DA, Zhang X, Lee Y, et al. Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction. The Journal of biological chemistry. 2013;288(2):915-926. 47. Eisenberg T, Abdellatif M, Schroeder S, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016;22(12):1428-1438. 48. Phu L, Rose CM, Tea JS, et al. Dynamic Regulation of Mitochondrial Import by the Ubiquitin System. Mol Cell. 2020;77(5):1107-1123 e1110. 49. Nezich CL, Wang C, Fogel AI, Youle RJ. MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5. J Cell Biol. 2015;210(3):435- 450. 50. Sowa ME, Bennett EJ, Gygi SP, Harper JW. Defining the human deubiquitinating enzyme interaction landscape. Cell.2009;138(2):389-403.

Claims

Attorney Docket No.103361-086WO1 WHAT IS CLAIMED IS: 1. method of treating, ameliorating and/or preventing cardiomyopathy in a subject in need thereof, the method comprising administering to the subject an effective amount of a small molecule USP30 inhibitor to inhibit, decrease, or reduce USP30 activity. 2. The method of claim 1, wherein the subject is mammal. 3. The method of any of claims 1-2, wherein the subject is a human. 4. The method of any of claims 1-3, wherein the cardiomyopathy is drug induced cardiomyopathy. 5. The method of any of claims 1-4, wherein the drug induced cardiomyopathy is caused by a drug selected from anthraquinone, antipsychotic phenothiazine derivates, arnica herb, arsenic, amphetamine, anabolic-androgenic steroids, azidothymidine, anagrelide, catecholamines, cytarabine, clozapine, cobalt, cocaine, chloroquine, cyclophosphamide, diazoxide, anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), ethanol, imatinib, isoproterenol, ephedrine, melarsoprol, methamphetamine, methylphenidate, minoxidil, mitomycin, mitoxantrone, paclitaxel, pentamidine, stibogluconate, sunitinib, trastuzumab, tricyclic antidepressants, or zidovudine. 6. The method of any of claims 1-5, wherein the drug is an anthracycline. 7. The method of any of claims 1-5, wherein the drug is doxorubicin. 8. The method of claim 6, wherein the method further comprises administering the small molecule USP30 inhibitors in combination with other therapies such as, radiation therapy, surgery, conventional chemotherapy, or with a combination of one or more additional therapies. 9. The method of claim 8, wherein the conventional chemotherapy comprises a chemotherapeutic agent inducing cardiomyopathy. Attorney Docket No.103361-086WO1 10. The method of claim 9, wherein the chemotherapeutic agent inducing cardiomyopathy comprises anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone). 11. The method of any of claims 1-3, wherein the cardiomyopathy is caused by a viral infection, coronary artery disease, or high blood pressure. 12. The method of any of claims 1-3, or 11, wherein the viral infection is caused by a virus selected from Coxsackie B and adenovirus, echoviruses, influenza H1N1, Epstein- Barr virus, rubella virus, varicella-zoster virus, mumps virus, measles virus, parvoviruses, yellow fever virus, dengue virus, polio virus, rabies virus and the viruses that cause hepatitis A virus and hepatitis C virus, and coronaviruses such as SARS- COV-2. 13. The method of claim 12, wherein the viral infection is caused by SARS-COV-2. 14. The method of any of claims 1-13, wherein the USP30 inhibitor is administered orally, topically, intravenously, subcutaneously, transcutaneous, transdermally, intramuscularly, intradermally, intraventricularly, intracranially, or intraperitoneally. 15. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a chemotherapeutic agent and an effective amount of a small molecule USP30 inhibitor to inhibit, decrease, or reduce USP30 activity. 16. The method of claim 15, wherein the chemotherapeutic agent comprises an anthracycline (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and/or mitoxantrone). 17. A chemotherapeutic regimen for the treatment of cancer, the regimen comprising a therapeutically effective amount of a chemotherapeutic agent to treat the cancer and an effective amount of a small molecule USP30 inhibitor to inhibit, decrease, or reduce USP30 activity. Attorney Docket No.103361-086WO1 18. The method of claim 15, wherein the chemotherapeutic an anthracycline (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and/or mitoxantrone).
EP23880797.8A 2022-10-19 2023-10-19 Compositions and methods for preventing cardiomyopathy Pending EP4604947A2 (en)

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CA2976741C (en) * 2015-03-30 2023-01-17 Mission Therapeutics Limited 1-cyano-pyrrolidine compounds as usp30 inhibitors
US10968172B2 (en) * 2017-05-15 2021-04-06 Mitobridge, Inc. USP30 inhibitors
AU2018346597B2 (en) * 2017-10-06 2023-07-13 Forma Therapeutics, Inc. Inhibiting Ubiquitin Specific Peptidase 30
WO2019079243A1 (en) * 2017-10-17 2019-04-25 Albert Einstein College Of Medicine, Inc. Mitofusin activators and uses thereof
US11845724B2 (en) * 2019-09-11 2023-12-19 Vincere Biosciences, Inc. USP30 inhibitors and uses thereof

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