WO2012174126A1 - Procédé d'inhibition de la dégradation des arnm induite par des codons d'arrêt - Google Patents

Procédé d'inhibition de la dégradation des arnm induite par des codons d'arrêt Download PDF

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Publication number
WO2012174126A1
WO2012174126A1 PCT/US2012/042272 US2012042272W WO2012174126A1 WO 2012174126 A1 WO2012174126 A1 WO 2012174126A1 US 2012042272 W US2012042272 W US 2012042272W WO 2012174126 A1 WO2012174126 A1 WO 2012174126A1
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substituted
unsubstituted
alkyl
group
hydrogen
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PCT/US2012/042272
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WO2012174126A8 (fr
Inventor
Tsafi PE'ERY.
Michael B. Mathews
Mainul Hoque
Hartmut M Hanauske-Abel
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Universyty Of Medicine And Dentistry Of New Jesey
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Priority to US14/126,342 priority Critical patent/US9849146B2/en
Publication of WO2012174126A1 publication Critical patent/WO2012174126A1/fr
Publication of WO2012174126A8 publication Critical patent/WO2012174126A8/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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

Definitions

  • the present invention relates to methods of treating nonsense-associated diseases and inhibiting nonsense-mediated mRNA decay by administering an inhibitor of NMD and a nonsense suppressor.
  • Nonsense-mediated decay is a cellular mechanism that selectively degrades faulty messenger RNA (“mRNA”) containing an out-of-place stop (nonsense) codon. If translated, such mRNAs would produce a shortened version of the encoded protein.
  • the NMD surveillance mechanism reduces or prevents the formation of these defective proteins and peptides. While NMD helps to protect against occasional mistakes that occur during RNA production, it also contributes to a number of genetic disorders collectively termed nonsense-associated diseases (“NADs"). Examples of NADs are cystic fibrosis and Hurler's syndrome. Depending on the gene affected and the mutation, prematurely terminated proteins may have low biological activity, no biological activity, or may even be harmful to biological functions.
  • NADs there is usually an insufficient amount of the full-length protein as a result of two processes: (1) the destruction of the defective mRNA by NMD; and (2) the synthesis of truncated protein from mRNA that escapes the destruction.
  • NMD is triggered by a premature stop codon located at least 50-55 nucleotides upstream of a splice junction in a multi-exon mRNA.
  • the present invention relates to methods for treating a NAD comprising administering to a patient suffering from a NAD an inhibitor of NMD and a nonsense suppressor, whereby degradation of NMD susceptible mRNA is decreased and translation termination at a misplaced nonsense codon is blocked.
  • R3 is hydrogen or a pharmacologically acceptable salt.
  • R7 and Re are each independently hydrogen, hydroxyl, halogen, nitro, cyano, sulfate, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclo, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkyl, alkoxy, alkylthioether, carboxyalkyl, carbonylalkyl, amino, NR9R9 1 , amido, or alkoxycarbonyl; or are taken together to form a substituted or unsubstit
  • the inhibitor of NAD is a compound of formula (III) or (IV):
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a hydrazaline compound and at least a second inhibitor of NMD, each at a low concentration at which the hydrazaline compound or the second NMD inhibitor alone would not inhibit NMD.
  • combination of the two components together can achieve effective inhibition, resulting in a synergistic effect.
  • R a is selected from halogen, Q-C 4 alkoxy, carbamoyl optionally substituted with one or two independently selected Q-C 4 alkyl or Q-C 4 alkoxy groups, phosphinoyl group optionally substituted with one or two independently selected CrC 4 alkyl or C C 4 alkoxy groups, morpholinyl group, pyridyl group, and R b group; and
  • nonsense suppressors include, but are not limited to, those characterized by formula (VIII),
  • X is (). S, or C3 ⁇ 4;
  • nucleosides as nonsense suppressors include, but are not limited to, those listed in US Patent No. 7,449,570, which are incorporated herein by reference as if all the examples disclosed therein are hereby specifically listed.
  • a referred compound of this type is Clitocine:
  • the nonsense suppressor is selected from the group comprising an aminoglycoside antibiotic, a compound such as is disclosed in US Patent Application 20090203752 or US Patent 7,449,570 and the like, or suppressor tRNA.
  • aminoglycoside antibiotics include Amikacin (Amikin), Gentamicin (Garamycin), G-Mycin, Jenamicin, Kanamycin (Kantrex), Neomycin ( My mecanicdin, Myciguent), Netilmicin (Netromycin), Paromomycin, Streptomycin, Tobramycin (Nebcin) and the like.
  • An exemplary compound of US patent 7,449,570 is Clitocine.
  • An exemplary compound of US Application 20090203752 is PTC124 ( Ataluren).
  • the RNA interfering agent may be an antisense nucleotide, siRNA, shRNA, or a DNA construct (e.g., a plasmid or a vector) encoding same.
  • siRNAs are double stranded RNA agents that have complementary to (i.e., able to basepair with) a portion of the target mRNA.
  • shRNA molecules are basically siRNA molecules wherein the two strands are connected by a loop thereby resulting in a formation of a hairpin-like structure.
  • complementarity to the target is 100%, but can be less if desired, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • 19 bases out of 21 bases may be base-paired.
  • 100% complementary to the target gene is required in order to effectively discern the target sequence from the other allelic sequence.
  • the small interfering RNA sequence needs to be of sufficient length to bring the small interfering RNA and target RNA together through complementary base-pairing interactions.
  • the small interfering RNA of the invention may be of varying lengths.
  • the length of the small interfering RNA is preferably greater than or equal to ten nucleotides and of sufficient length to stably interact with the target RNA; specifically 15-30 nucleotides; more specifically any integer between 15 and 30 nucleotides, such as 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30.
  • all of the present inventive methods can comprise the administration of the compound, in the presence or absence of an agent that enhances its efficacy, or the methods can further comprise the administration of other suitable components, such as compounds that suppress nonsense codon recognition.
  • Such suppression reduces the efficiency of translation termination at the misplaced nonsense mutations by administering certain pharmacological compounds or suppressor tRNAs. Examples of suppressor tRNAs and other pharmacological compounds that suppress nonsense mutations should be readily apparent to one skilled in the art.
  • targeting moiety refers to any molecule or agent that specifically recognizes and binds to a cellsurface receptor, such that the targeting moiety directs the delivery of the compound to a population of cells on which surface the receptor is expressed.
  • Targeting moieties include, but are not limited to, antibodies, or fragments thereof, peptides, hormones, growth factors, cytokines, and any other naturally or non-naturally existing ligands, which bind to cell surface receptors.
  • linker refers to any agent or molecule that bridges the compound to the targeting moiety.
  • Suitable methods of administering a compound of the present invention are known, and, although more than one route can be used to administer a particular composition, a particular route can provide a more immediate and more effective response than another route.
  • compositions that include compounds of formula (I)- (IV) can be administered topically or systemically (intravenously or subcutaneously). More particularly, such administration can be orally; parenterally, i.e., by subcutaneous, intravascular, or intramuscular injection; intraperitoneally; intrathecally; or by topical application, e.g., to skin or eyes, or by application to the mucous membranes of the nose, throat, bronchial tree, genital tract, or rectum, and so forth. They may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid form such as tablets, capsules, powders, solutions, suspensions, or emulsions.
  • Formulations suitable for oral administration of compositions which include compounds of the present invention can consist of (a) liquid solutions, such as an effective amount of the compounds dissolved in diluents, such as water or saline, (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solids or granules, (c) suspensions in an appropriate liquid, and (d) suitable emulsions.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • water, saline, aqueous dextrose and related sugar solution, and glycols such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.
  • the active compounds or their physiologically tolerated derivatives such as salts, esters, or amides
  • a physiologically acceptable liquid for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • suitable propellants for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • suitable propellants for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • suitable propellants for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • suitable propellants for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • the agents which block intracellular hypusine formation in accordance with the present invention, may also be administered from a non- pressurized container such as a nebulizer or atomizer.
  • the active compounds or their physiologically tolerated derivatives such as, salts, esters, or amides, are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.
  • the cell sample should comprise cells where the mRNA containing premature stop codon is expressed, and therefore, the nature of the cell sample would ultimately depend on the nature of the mRNA which is to be tested.
  • the means for inhibiting eIF5A are also known in the art and/or discussed in the instant specification.
  • eIF5A may be inhibited using the compounds according to the Formulae IIV, with the limitations for the side chain substitutions as described above.
  • RNAi agents may be used, such as antisense nucleotides and/or siRNA (or shRNA).
  • suitable targets eIF5A, DOHH and DHS
  • shRNA shRNA
  • the sequences for the suitable targets eIF5A, DOHH and DHS
  • the algorithms for selecting suitable RNA I agents are also described in the prior art.
  • the methods of culturing cells, extracting mRNA, and obtaining cDNA from mRNA are well known and do not need to be described in details herein.
  • 293T cells transfected with a FLAG-tagged eIF5A expression vector were simultaneously treated with ciclopirox ("CPX") or deferiprone (“DEF").
  • CPX ciclopirox
  • DEF deferiprone
  • the NIH-335 antibody reacts preferentially with post-translationally modified eIF5A.
  • CPX reduced the appearance of mature eIF5A over the 3-30 ⁇ concentration range, while DEF was effective at 200-400 ⁇ .
  • the compounds did not alter the expression of actin. Comparable results have been obtained in other cell types by spermidine labeling of eIF5A.
  • deferoxamine (“DFOX"; DesferalTM) was used as a control compound.
  • DFOX a metal-binding hydroxamate like CPX and Agent P2 (FIG. 3), is a globally used medicinal iron chelator. Referring to FIGs.
  • 293T cells transfected with FLAG-eIF5A were untreated (-) or treated with GC7 (10 ⁇ ) or CPX (30 ⁇ ), P2 (30 ⁇ ), DEF (250 ⁇ ), or DFOX (10 ⁇ ).
  • WCE prepared at 24 hours post-transfection was immunoprecipitated with anti- FLAG antibody. Complexes that immunoprecipitated with anti-FLAG antibody were immunoblotted and probed with antibodies against DOHH. Endogenous DOHH co- immunoprecipitated with FLAG-eIF5A, and this association was largely prevented by treatment with CPX or DEF (FIG. 2D, top panel).
  • FF firefly luciferase
  • construct II Human 293 cells were co-transfected with a test plasmid (construct I) that is sensitive to NMD and a matched control plasmid (construct II).
  • the constructs contain firefly luciferase (FF) reporter genes and are based on studies in the HIV-1 system (Hoque M, Hanauske-Abel HM, Palumbo P, Saxena D, D'Alliessi Gandolfi D, Park MH, Pe'ery T, Mathews MB. Retrovirology. 2009 Oct 13;6:90).
  • a plasmid expressing Renilla luciferase (Ren) directed by the CMV promoter was included as a reference and internal control.
  • Fig. 7 shows that NMD in the thalassemia model system of Figure 6 is inhibited by the drugs ciclopirox (CPX), deferiprone (DEF), and hydralazine (HYD) which all prevent eIF5A modification, resulting in increased gene expression.
  • CPX drugs ciclopirox
  • DEF deferiprone
  • HTD hydralazine
  • This inhibition of NMD is seen at drug concentrations that in a dose-dependent manner interfere with DOHH function, namely 15 / 30 ⁇ CPX, 125 / 250 ⁇ DEF, and 200 / 400 ⁇ HYD.
  • These experiments were carried out in the well-authenticated assay system using vectors containing NMD signals associated with B°39-thalassemia (Woeller CF, Gaspari M, Isken O, Maquat L.: EMBO Rep.
  • Fig. 9 exemplifies the effect of combining several NMD inhibitors, each at a concentration ineffective for NMD inhibition, in order to achieve a degree of NMD inhibition that reaches statistical significance.
  • DEF at 125 ⁇ and HYD at 200 ⁇ each compound ineffective individually, reach effectiveness when combined.

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Abstract

La présente invention concerne des procédés de traitement d'une NAD (maladie associée à des codons d'arrêt) comprenant l'administration à un patient atteint d'une NAD d'un inhibiteur de NMD (dégradation induite par des codons d'arrêt) et d'un agent de suppression des codons d'arrêt, la dégradation des ARNm sensibles à la NMD étant ainsi réduite et la terminaison de la traduction au niveau d'un codon d'arrêt au mauvais endroit étant ainsi bloquée.
PCT/US2012/042272 2009-07-20 2012-06-13 Procédé d'inhibition de la dégradation des arnm induite par des codons d'arrêt WO2012174126A1 (fr)

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US14/126,342 US9849146B2 (en) 2009-07-20 2012-06-13 Inhibition of nonsense mediated mRNA decay by drugs that prevent hypusination of eukaryotic initiation factor 5A

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US49637811P 2011-06-13 2011-06-13
US60/496,378 2011-06-13

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015026852A1 (fr) * 2013-08-19 2015-02-26 Rutgers, The State University Of New Jersey Procédé pour induire une réponse immunitaire anti-rétrovirale par une anti-apoptose induite par rétro-virus d'effet opposé
US9227956B2 (en) 2013-04-17 2016-01-05 Pfizer Inc. Substituted amide compounds
EP2892525A4 (fr) * 2012-09-10 2016-08-03 Univ Nevada Méthodes de traitement de la dystrophie musculaire
US9707210B2 (en) 2013-03-15 2017-07-18 Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno Methods of treating muscular dystrophy
EP3417860A1 (fr) * 2017-06-19 2018-12-26 Asociación Centro de Investigación Cooperativa en Biociencias - CIC bioGUNE Utilisation de ciclopirox en tant que modulateur de la biosynthèse du groupe hémique et dans le traitement de porphyries et d'autres maladies
US11001588B2 (en) 2018-09-19 2021-05-11 Forma Therapeutics, Inc. Activating pyruvate kinase R and mutants thereof
US11014927B2 (en) 2017-03-20 2021-05-25 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US11071725B2 (en) 2018-09-19 2021-07-27 Forma Therapeutics, Inc. Activating pyruvate kinase R

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011005566A2 (fr) * 2009-06-23 2011-01-13 University Of Miami Siarn ciblé contre un aptamère pour inhiber une dégradation à médiation par un non-sens
US20110039911A1 (en) * 2009-07-20 2011-02-17 Pe Ery Tsafi METHOD OF INHIBITING NONSENSE-MEDIATED mRNA DECAY

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011005566A2 (fr) * 2009-06-23 2011-01-13 University Of Miami Siarn ciblé contre un aptamère pour inhiber une dégradation à médiation par un non-sens
US20110039911A1 (en) * 2009-07-20 2011-02-17 Pe Ery Tsafi METHOD OF INHIBITING NONSENSE-MEDIATED mRNA DECAY

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10272069B2 (en) 2012-09-10 2019-04-30 Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno Methods of treating muscular dystrophy
US10398680B2 (en) 2012-09-10 2019-09-03 Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno Methods of treating muscular dystrophy
EP2892525A4 (fr) * 2012-09-10 2016-08-03 Univ Nevada Méthodes de traitement de la dystrophie musculaire
US9566310B2 (en) 2012-09-10 2017-02-14 Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno Methods of treating muscular dystrophy
US9980943B2 (en) 2013-03-15 2018-05-29 Board Of Regents Of The Nevada Systems Of Higher Education On Behalf Of The Nevada, Reno Methods of treating muscular dystrophy
US10537553B2 (en) 2013-03-15 2020-01-21 Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno Methods of treating muscular dystrophy
US9707210B2 (en) 2013-03-15 2017-07-18 Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno Methods of treating muscular dystrophy
US10206903B2 (en) 2013-03-15 2019-02-19 Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno Methods of treating muscular dystrophy
US9227956B2 (en) 2013-04-17 2016-01-05 Pfizer Inc. Substituted amide compounds
WO2015026852A1 (fr) * 2013-08-19 2015-02-26 Rutgers, The State University Of New Jersey Procédé pour induire une réponse immunitaire anti-rétrovirale par une anti-apoptose induite par rétro-virus d'effet opposé
US11014927B2 (en) 2017-03-20 2021-05-25 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US11396513B2 (en) 2017-03-20 2022-07-26 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US11649242B2 (en) 2017-03-20 2023-05-16 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
WO2018233914A1 (fr) * 2017-06-19 2018-12-27 Asociación Centro De Investigación Cooperativa En Biociencias-Cic Biogune Utilisation de ciclopirox en tant que modulateur de la biosynthèse du groupe hème et dans le traitement de porphyries et d'autres maladies
EP3417860A1 (fr) * 2017-06-19 2018-12-26 Asociación Centro de Investigación Cooperativa en Biociencias - CIC bioGUNE Utilisation de ciclopirox en tant que modulateur de la biosynthèse du groupe hémique et dans le traitement de porphyries et d'autres maladies
US11337966B2 (en) 2017-06-19 2022-05-24 Asociación Centro De Investigación Cooperativa En Biociencias-Cic Biogune Use of ciclopirox as a modulator of the heme group biosynthesis and in the treatment of porphyrias and other diseases
US11001588B2 (en) 2018-09-19 2021-05-11 Forma Therapeutics, Inc. Activating pyruvate kinase R and mutants thereof
US11071725B2 (en) 2018-09-19 2021-07-27 Forma Therapeutics, Inc. Activating pyruvate kinase R
US11844787B2 (en) 2018-09-19 2023-12-19 Novo Nordisk Health Care Ag Activating pyruvate kinase R
US11980611B2 (en) 2018-09-19 2024-05-14 Novo Nordisk Health Care Ag Treating sickle cell disease with a pyruvate kinase R activating compound

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