Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents

Definitions

• the melanocortin 4 receptor is a heterotrimeric G-protein-coupled receptor that transduces signals by activating adenylate cyclase.
• MC4R is primarily expressed in neuronal tissue and plays a role in controlling feeding behavior and energy homeostasis by, for example, integrating an agonist signal provided by the a-melanocyte stimulating hormone (a-MSH), and an antagonist signal provided by the agouti -related peptide (AGRP).
• a-MSH a-melanocyte stimulating hormone
• AGRP agouti -related peptide
• MC4R is a part of the leptin-melanocortin pathway, also known as the POMC-MC4R pathway, which includes a number of proteins such as leptin, leptin receptors, pro- opiomelanocortin (POMC), and prohormone convertases including PCSK1, a-MSH, and others.
• POMC pro- opiomelanocortin
• PCSK1, a-MSH prohormone convertases
• the hypothalamic POMC-MC4R pathway is part of the regulatory network of appetite and body weight.
• the present disclosure features, inter alia, treatments for diseases, disorders, and conditions related to the melanocortin-4 receptor (MC4R) pathway.
• the present disclosure comprises a method of treating a disease, disorder, or condition in a subject having an MC4R pathway agonizable gene with a compound (e.g., an MC4R agonist) or compositions thereof.
• a compound e.g., an MC4R agonist
• the MC4R agonist is a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), (e.g, as described herein) or a pharmaceutically acceptable salt thereof.
• the subject has or is identified as having a mutation (e.g., a substitution mutation, a deletion mutation, or a polymorphism, e.g., a loss of function mutation) or an epigenetic modification in or at an MC4R pathway agonizable gene, e.g., as described herein.
• a mutation e.g., a substitution mutation, a deletion mutation, or a polymorphism, e.g., a loss of function mutation
• an epigenetic modification in or at an MC4R pathway agonizable gene e.g., as described herein.
• the MC4R pathway agonizable gene is selected from ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMRI, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG2, IRS1, IRS4, KCTD15, KIDINS220, MCHR1, MSRA, NDN, NEGRI, NLGN2, NPY, NR0B2, NTRK2, PCNT, PCSK2, PHF6, PMCH, PPARG, PY
• the MC4R pathway agonizable gene is selected from ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMRI, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG2, IRS1, IRS4, KCTD15, KIDINS220, MCHR1, MSRA, NDN, NEGRI, NLGN2, NPY, NR0B2, NTRK2, PCNT, PCSK2, PHF6, PMCH, PPARG, PY
• the MC4R pathway agonizable gene is selected from RAH and SRC1. In some embodiments, the MC4R pathway agonizable gene is RAH. In some embodiments, the MC4R pathway agonizable gene is SRC1. In some embodiments, the MC4R pathway agonizable gene is TRPC5. In some embodiments, the MC4R pathway agonizable gene is PHIP. In some embodiments, the MC4R pathway agonizable gene is PCSK1 N221D. In some embodiments, the MC4R pathway agonizable gene is selected from a gene listed in Table 1, e.g., described herein.
• the MC4R pathway agonizable gene is POMC, PCSK1, LEPR, LEP, MC4R, SDCCAG8, SH2B1, CPE, ALMS1, BBS1, BBS2, BBS4, BBS5, BBS6, BBS7, BBS8, BBS9, BBS10, BBS12, BBS18, BBS20, GNAS, MC3R, NHLH2, SIM1, BDNF, NTRK2, MAGEL2, or a 16pl 1.2 deletion.
• the subject carries, or is identified as carrying, a mutation in a MC4R pathway agonizable gene. In an embodiment, the subject is, or is identified as being, heterozygous for a mutation in the MC4R pathway agonizable gene.
• a heterozygous subject carries, or is identified as carrying, a non-functional, e.g., mutant, e.g., null mutant, allele of the MC4R pathway agonizable gene and a functional or wildtype allele of the MC4R pathway agonizable gene.
• a heterozygous subject carries, or is identified as carrying, a first non-functional, e.g., mutant, e.g., null mutant, allele of the MC4R pathway agonizable gene and a second non-functional or mutant, e.g., null mutant, allele of the MC4R pathway agonizable gene.
• the subject is a compound heterozygous carrier having two distinct non-functional alleles.
• the subject is, or is identified as, homozygous for a non- functional, e.g., mutant, e.g., null mutant, allele of an MC4R pathway agonizable gene.
• the subject carries, or is identified as carrying, a mutation in a second MC4R pathway agonizable gene.
• the subject is, or is identified as being, heterozygous for a mutation in the second MC4R pathway agonizable gene.
• a heterozygous subject carries, or is identified as carrying, a non-functional, e.g., mutant, e.g., null mutant, allele of the second MC4R pathway agonizable gene and a functional or wildtype, allele of the second MC4R pathway agonizable gene.
• a heterozygous subject carries, or is identified as carrying, a first non- functional, e.g., mutant, e.g., null mutant, allele of the second MC4R pathway agonizable gene and a second non-functional or mutant, e.g., null mutant, allele of second the MC4R pathway agonizable gene.
• the subject is a compound heterozygous carrier having two distinct non-functional alleles.
• the subject is, or is identified as, homozygous for a non- functional, e.g., mutant, e.g., null mutant, allele of a second MC4R pathway agonizable gene.
• the MC4R agonist e.g., a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt thereof, may be provided as a composition (e.g., a pharmaceutical composition) with a pharmaceutically acceptable excipient.
• the pharmaceutically acceptable excipient comprises a polyethylene glycol (e.g., a modified polyethylene glycol), a lipid (e.g., a neutral lipid or a phospholipid).
• the pharmaceutically acceptable excipient comprises a modified polyethylene glycol.
• the pharmaceutically acceptable excipient comprises a lipid, such as a neutral diacyl lipid or a phospholipid.
• the MC4R agonist or composition thereof may be provided in a unit dosage form.
• the unit dosage form may comprise between about 0.01 mg to 100 mg of the MC4R agonist.
• the unit dosage form comprises between 0.1 mg and 100 mg, e.g., between 0.1 mg and 50 mg, 0.1 mg and 25 mg, 0.1 mg and 10 mg, 1 mg and 100 mg, 1 mg and 50 mg, 1 mg and 25 mg, 1 mg and 10 mg, 5 mg and 100 mg, 5 mg and 50 mg, 5 mg and 25 mg, 5 mg and 15 mg, or 5 mg and 10 mg.
• the MC4R agonist or composition thereof may be administered to a subject daily, weekly or monthly. In an embodiment, the MC4R agonist or composition thereof is administered daily, e.g., once daily, twice daily, or three times daily. In an embodiment, the MC4R agonist or composition thereof is administered weekly, e.g., once every week, once every two weeks, once every three weeks.
• the MC4R agonist or composition thereof is administered daily over a period of at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or at least 1, 2, 3, 4 years or more.
• the method comprises administering the MC4R agonist or composition thereof in a unit dosage form suitable for injection, e.g., subcutaneous injection, to the subject.
• the unit dosage form is disposed within a delivery device, e.g., a syringe (e.g., prefilled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., implantable infusion pump), or an osmotic delivery system.
• the MC4R agonist is administered subcutaneously, e.g., by subcutaneous injection.
• the subject is obese, e.g., severely obese. In embodiments, the subject has early onset severe obesity.
• the subject is hyperphagic. In embodiments, the subject experiences severe hunger. In embodiments, the subject has a body mass index (BMI) greater than 25 kg/m 2 (e.g., ⁇ 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m 2 or greater) prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration.
• BMI body mass index
• the subject has a body mass index (BMI) greater than 35 kg/m 2 (e.g., ⁇ 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m 2 or greater) prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration.
• BMI body mass index
• the subject has a body mass index (BMI) greater than 40 kg/m 2 (e.g., ⁇ 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg/m 2 or greater) prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration.
• BMI body mass index
• the subject has a body mass index (BMI) greater than 45 kg/m 2 (e.g., ⁇ 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg/m 2 or greater) prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration.
• BMI body mass index
• the subject has a BMI higher than the 85-95th percentile prior to administration of the MC4R agonist or composition thereof, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration.
• the subject has failed one or more previous therapies, e.g., exercise, diet, or behavioral therapies, prior to administration of the MC4R agonist or composition thereof, e.g., at the time the agonist is prescribed, or at the time of the first administration.
• previous therapies e.g., exercise, diet, or behavioral therapies
• the subject has a lower body weight after administration of the MC4R agonist or composition thereof than before administration of the agonist.
• administration of the MC4R agonist or composition thereof results in a reduction of weight in the subject compared to the weight of the subject before treatment of about 1 kg to 3 kg after 1 week of treatment, or about 1 kg to 6 kg after 2 weeks of treatment, or about 2 kg to 12 kg after 4 weeks of treatment, or about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment.
• administration of the MC4R agonist or composition thereof results in a reduction of BMI by about 1%, 2%, 3%, 5%, 6%, 7%, 8%, 9%, 10%, or more, e.g., by at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks or longer.
• administering results in no detectable/ significant decrease in resting energy expenditure (REE) in the subject, e.g., over a period of 24 hours, one week, or 30 days or longer, e.g., as compared to a control REE (e.g., the REE in the subject prior to treatment or a predetermined REE, e.g., in subjects of similar pre-treatment BMI, e.g., when expressed as REE per kg of lean body mass).
• REE resting energy expenditure
• administration of the MC4R agonist or composition thereof results in a reduction in food intake of at least 5 kcal/kg/day, e.g., 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 or more kcal/kg/day.
• the reduction in food intake is relative to the food intake at baseline.
• the baseline food intake is at least 100 kcal/kg/day, e.g., for a pediatric subject at about 1 year of age.
• the baseline food intake is at least 40 kcal/kg/day, e.g., for a pediatric subject, e.g., in late adolescence.
• administration of the MC4R agonist or composition thereof results in a reduction in waist circumference of the subject compared to a control (e.g., the waist circumference of the subject prior to treatment), as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.
• administration of the MC4R agonist or composition thereof results in no detectable increase in blood pressure (e.g., diastolic and/or systolic blood pressure) of the subject compared to the blood pressure of the subject prior to treatment, as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.
• administration of the MC4R agonist or composition thereof results in a reduction in blood pressure (e.g., diastolic and/or systolic blood pressure) of the subject compared to the blood pressure of the subject prior to treatment, as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.
• administration of the MC4R agonist or composition thereof results in a reduction in systolic blood of the subject of at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg or more) compared to the blood pressure of the subject prior to treatment, as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.
• 3 mmHg e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg or more
• administration of the MC4R agonist or composition thereof results in a reduction in diastolic blood pressure of the subject of at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg or more) compared to the blood pressure of the subject prior to treatment, as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.
• 4 mmHg e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg or more
• administration of the MC4R agonist or composition thereof results in a reduction of hunger in a subject.
• the reduction of hunger may result in a reduction of food intake, decrease in resting energy expenditure (REE), reduction of weight, reduction in waist circumference, and/or reduction in blood pressure in the subject.
• REE resting energy expenditure
• the subject is a mammal, e.g., a human.
• the method further comprises acquiring knowledge of the genotype of the subject, e.g., acquiring knowledge of the genotype of an MC4R pathway agonizable gene, e.g., a gene listed in Table 1.
• the knowledge is acquired directly, e.g., from a sample (e.g., a blood, serum, urine, or tissue (e.g., biopsy) sample) from the subject.
• the MC4R agonist or composition thereof is administered in response to the detection of a predetermined sequence, e.g., a mutation, MC4R pathway agonizable gene, e.g., a gene listed in Table 1.
• a predetermined sequence e.g., a mutation, MC4R pathway agonizable gene, e.g., a gene listed in Table 1.
• the predetermined sequence e.g., mutation
• the predetermined sequence, e.g., mutation is detected in the subject.
• the predetermined sequence, e.g., mutation is detected in a nucleic acid molecule or a polypeptide in a sample from the subject.
• the sample comprises cells from a blood, serum, urine, or tissue (e.g., biopsy) from the subject.
• the method comprises acquiring knowledge of the genotype of the subject, e.g., acquiring knowledge of the genotype of, e.g., of a mutation in a gene listed in
• the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I) is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 (SEQ ID NO: 140) or a pharmaceutically acceptable salt thereof.
• the compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof.
• the compound of Formula (II) is Hydantoin(C(O)-(Arg-Gly))- cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 (SEQ ID NO: 13) or a pharmaceutically acceptable salt thereof.
• the compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is formulated as a pharmaceutical composition.
• the present disclosure is based at least in part on the discovery that targeting certain defects in the POMC-MC4R pathway, e.g., such as mutations in an MC4R pathway agonizable gene by using a MC4R agonist, may lead to significant weight loss, decrease in hunger, and/or an increase in energy expenditure in obese subjects.
• the disclosure is also based in part on the discovery that obese subjects having a defect (e.g., genetic defect) in an MC4R pathway agonizable genes are likely to exhibit a significantly greater response (e.g., in decreasing body weight and/or hunger and/or increasing energy expenditure) to an MC4R agonist than obese subjects not having such a defect.
• a MC4R agonist such as a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), (e.g., as described herein), e.g., setmelanotide (i.e., Ac-Arg-c(Cys-D-Ala-His-D-Phe- Arg-Trp-Cys)-NH 2 , SEQ ID NO: 140) or a pharmaceutically acceptable salt thereof, can act to replace a missing MC4R signaling step in subjects having a genetic defect an MC4R pathway agonizable gene.
• setmelanotide i.e., Ac-Arg-c(Cys-D-Ala-His-D-Phe- Arg-Trp-Cys
• a MC4R agonist such as setmelanotide
• general obesity e.g., wild-type obesity and/or obesity in a subject lacking an identifiable MC4R pathway deficit.
• the methods and compositions described herein provide an optimized approach to restore MC4R pathway function in subjects with genetic disorders (e.g., genetic deficiencies in one or more genes of the P0MC-MC4R pathway) such as Smith-Magenis syndrome, thereby decreasing the extreme hyperphagia and obesity seen in these subjects.
• MC4R pathway agonizable gene Provided herein are methods to treat subjects having a genetic defect in an MC4R pathway agonizable gene, as well as methods to identify/select subjects that have such defects and/or that are likely to respond to a MC4R agonist (e.g., more likely to respond to a MC4R agonist than wild-type obese subjects).
• “Directly acquiring” means performing a physical process (e.g., performing a synthetic or analytical method) to obtain the physical entity, value, or knowledge.
• “Indirectly acquiring” refers to receiving the physical entity, value, or knowledge from another party or source (e.g., a third- party laboratory that directly acquired the physical entity, value, or knowledge).
• Directly acquiring a physical entity includes performing a process that includes a physical change in a physical substance, e.g., a starting material. Exemplary changes include making a physical entity from two or more starting materials, shearing or fragmenting a substance, separating or purifying a substance, combining two or more separate entities into a mixture, performing a chemical reaction that includes breaking or forming a covalent or non-covalent bond. Directly acquiring a value or knowledge includes performing a process that includes a physical change in a sample or another substance.
• Examples include performing an analytical process which includes a physical change in a substance, e.g., a sample, analyte, or reagent (sometimes referred to herein as “physical analysis”), performing an analytical method, e.g., a method which includes one or more of the following: separating or purifying a substance, e.g., an analyte, or a fragment or other derivative thereof, from another substance; combining an analyte, or fragment or other derivative thereof, with another substance, e.g., a buffer, solvent, or reactant; or changing the structure of an analyte, or a fragment or other derivative thereof, e.g., by breaking or forming a covalent or non-covalent bond, between a first and a second atom of the analyte; or by changing the structure of a reagent, or a fragment or other derivative thereof, e.g., by breaking or forming a covalent or non-covalent bond, between a first and
• the term “functional,” as applied to an allele, e.g., of a MC4R pathway agonizable gene, refers to an allele having , e.g., at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wildtype allele.
• nonfunctional refers to an allele which has less than 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wildtype allele.
• a nonfunctional allele is an allele of the gene that is other than a functional allele, as the term functional allele is defined herein.
• a functional allele has at least 20% of the activity of a reference allele a nonfunctional allele is an allele with less than 20% of the activity.
• M4R pathway agonizable gene refers to a gene associated with a phenotype which can be modulated, e.g., ameliorated or lessened, by modulating MC4R, e.g., agonizing MC4R, e.g., with an MC4R agonist.
• the phenotype is hyperphagia, appetite, unwanted appetite, obesity, weight, body mass, or a metabolic syndrome (e.g., diabetes) and the phenotype is, e.g., modulated, e.g., reduced or ameliorated.
• the term “MC4R pathway agonizable gene” does not include the melanocortin 4 receptor (MC4R) gene.
• the term “MC4R pathway agonizable gene” does not include POMC.
• the MC4R pathway agonizable gene does not comprise any one of POMC, Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1, also called PC1/3), MAGE-like-2 (MAGEL2), leptin receptor (leptin-R), leptin, 5 -hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix loop helix 2 (NhHL2, also called NSCL2), pro-hormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Siml).
• the MC4R pathway agonizable gene does not comprise any gene disclosed in W02013/102047 or WO 2017/059076
• At least one of the MC4R alleles is functional, e.g., it has at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wildtype allele, e.g., as measured by a functional assay.
• one of the MC4R alleles is functional.
• both MC4R alleles are functional.
• the subject is heterozygous at the MC4R gene and both alleles are functional.
• the subject is homozygous at the MC4R gene for a functional allele.
• both MC4R alleles are nonfunctional.
• a nonfunctional allele is an allele which is not functional, as functional is defined herein.
• the subject is heterozygous at the MC4R gene and both alleles are nonfunctional.
• the subject is homozygous at the MC4R gene for a nonfunctional allele.
• At least one allele of an MC4R pathway agonizable gene other than MC4R is functional, e.g., it has at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wildtype allele, e.g., as measured by a functional assay.
• one allele of an MC4R pathway agonizable gene other than MC4R is functional.
• both alleles of an MC4R pathway agonizable gene other than MC4R are functional.
• the subject is heterozygous at an MC4R pathway agonizable gene other than MC4R and both alleles are functional.
• the subject is homozygous at an MC4R pathway agonizable gene other than MC4R for a functional allele.
• both MC4R alleles are nonfunctional.
• a nonfunctional allele is an allele which is not functional, as functional is defined herein.
• the subject is heterozygous at the MC4R gene and both alleles are nonfunctional.
• the subject is homozygous at the MC4R gene for a nonfunctional allele.
• an epigenetic modification e.g., a histone modification, e.g., acetylation or nucleobase methylation, e.g., cytosine methylation
• a histone modification e.g., acetylation or nucleobase methylation, e.g., cytosine methylation
• nucleobase methylation e.g., cytosine methylation
• the epigenetic modification is associated with an MC4R pathway agonizable gene. In an embodiment, the epigenetic modification is associated with MC4R.
• the epigenetic modification is associated with an MC4R pathway agonizable gene other than MC4R.
• the MC4R pathway agonizable gene does not comprise any one of POMC, Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1, also called PC1/3), MAGE-like-2 (MAGEL2), leptin receptor (leptin-R), leptin, 5 -hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix loop helix 2 (NhHL2, also called NSCL2), pro-hormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Siml).
• PCSK1 Proprotein Convertase Subtilisin/Kexin Type 1
• MAGEL2 MAGE-like-2
• leptin receptor leptin receptor
• the MC4R pathway agonizable gene does not comprise any gene disclosed in W02013/102047 or WO 2017/059076, the full contents of each of which is incorporated herein by reference in its entirety.
• the term “obese” refers to a subject having a body mass index (BMI) within the ranges defined as “obese” by the Center for Disease Control (see, e.g., URL.cdc.gov/obesity/ defming.html and www.cdc.gov/obesity/childhood-/defming.html, last accessed on August 26, 2012) or as defined by “Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults” from the National Institutes of Health.
• BMI is obtained by dividing a subject’s weight, e.g., in kilograms (kg) by the square of the subject’s height, e.g., in meter (m).
• a subject’s weight e.g., in kilograms (kg) by the square of the subject’s height, e.g., in meter (m).
• an adult who has a BMI of 30 kg/m 2 or higher is considered obese.
• an adult with a BMI of 25.0 to 29.9 kg/m 2 is considered overweight; an adult with a BMI of 18.5 to 24.9 kg/m 2 is considered to have a normal or healthy weight range; and an adult with a BMI of less than 18.5 kg/m 2 is considered to be underweight.
• an adult having a height of 5 feet, 9 inches with a body weight of 203 pounds or more is considered obese.
• obese refers to a subject having a BMI at or above the 85 th to 95 th percentile for children and teens of the same age and sex.
• a “severely obese” subject or a subject having “severe obesity” refers to a subject having a BMI of 35 kg/m 2 or higher, e.g., 40 kg/m 2 or higher.
• a severely obese subject is over 100% over the ideal (normal, healthy) body weight.
• onset e.g., as in early onset obesity, refers to an onset (e.g., first occurrence of one or more symptoms of a disorder, e.g., a disorder described herein, e.g., obesity) that occurs in a subject before adulthood, e.g., during childhood, e.g., when the subject is less 18 years of age or younger (e.g., 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year of age or younger, or during adolescence, e.g., when the child is younger than 12 years of age or when the child is younger than 6 years of age).
• a disorder e.g., a disorder described herein, e.g., obesity
• metabolic syndrome refers to a group of symptoms that occur together and increase the risk for coronary artery disease, stroke, and type 2 diabetes. According to the American Heart Association and the National Heart, Lung, and Blood Institute, metabolic syndrome also referred to as Syndrome X) is present if a subject has three or more of the following signs: 1) Blood pressure equal to or higher than 130/85 mmHg;
• Metabolic syndrome can be diagnosed by testing subject’s blood pressure, blood glucose level, HDL cholesterol level, LDL cholesterol level, total cholesterol level, and triglyceride level.
• agonist refers to any chemical compound, either naturally occurring or synthetic, that, upon interacting with (e.g., binding to) its target, e.g., MC4R, raises the signaling activity of MC4R above its basal level.
• An agonist can be a superagonist (i.e. a compound that is capable of producing a greater maximal response than the endogenous agonist for the target receptor, and thus has an efficacy of more than 100%), a full agonist (i.e. a compound that elicits a maximal response following receptor occupation and activation) or a partial agonist (i.e. a compounds that can activate receptors but are unable to elicit the maximal response of the receptor system).
• treating includes achieving one or more of the following results: reducing the body weight (as measured, for example, by a body mass index (BMI) and/or body weight), e.g., compared to a control (e.g., body weight before treatment or a predetermined body weight); reducing the waist circumference, e.g., compared to a control (e.g., waist circumference before treatment or a predetermined waist circumference); reducing the hunger level, e.g., compared to a control (e.g., hunger level before treatment or a predetermined hunger level); increasing the resting energy expenditure (REE), e.g., compared to a control (e.g., REE before treatment or a predetermined REE); decreasing the food intake, e.g., compared to a control level (e.g., before treatment or a predetermined food intake); ameliorating or improving a clinical symptom or indicators associated with a disorder described herein such as obesity, Prader Willi Syndrome
• Delaying, inhibiting or preventing the progression of the obesity includes for example, delaying, inhibiting or preventing the progression of a subject having normal weight to obesity.
• a control is a value of a parameter measured before treatment by a MC4R agonist described herein or a predetermined value.
• the term “treating” further includes partially or totally reducing the risk for coronary artery disease, stroke, and type 2 diabetes associated with the metabolic syndrome as well as ameliorating or improving a clinical symptom or signs of metabolic syndrome associated with metabolic syndrome, such as any one or more of the five indicators listed above.
• the term “treating” includes delaying, inhibiting or preventing the progression of parameters associated with the metabolic syndrome, including insulin resistance, glucose clearance and parameters of cardiovascular disease including heart rate and blood pressure.
• inhibition can include a reduction in a certain parameter, such as a parameter described herein.
• a parameter e.g., activity
• inhibition of a parameter can be at least 5%, 10%, 20%, 30%, 40%, or more is included by this term. Thus, inhibition need not be 100%.
• “Prophylactic treatment” refers to treatment before onset of obesity to prevent, inhibit or reduce its occurrence.
• subject refers to a mammal, e.g., a human.
• Subject can also refer to an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
• companion animals e.g., dogs, cats, and the like
• farm animals e.g., cows, sheep, pigs, horses, and the like
• laboratory animals e.g., rats, mice, guinea pigs, and the like.
• mutation can refer to an altered nucleic acid sequence of a gene or fragment thereof compared to a wild-type sequence.
• a mutation can include a point mutation, frame-shift mutation, missense mutation, inversion, deletion, insertion, truncation, chromosomal translocation.
• a mutation can result in the gene or fragment thereof coding for a non-functional protein, a protein with reduced activity (or a partially functional protein), or a protein with altered activity.
• a “loss of function” mutation refers to a mutation that results in the gene or fragment thereof coding for a non-functional protein, which has substantially reduced activity compared to its wild-type counterpart (e.g., a non-functional protein has less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less activity than its wild-type counterpart).
• “partial loss of function” mutation refers to a mutation that results in the gene or fragment thereof coding for a partially functional protein, which has reduced activity compared to its wild-type counterpart (e.g., a partially functional protein has less than 50% and greater than 10% of the activity of its wild-type counterpart).
• heterozygous refers to the presence of two different alleles (having different nucleic acid sequences) for a given gene in a subject.
• heterozygous mutation can refer to the presence of a mutation on one allele for a given gene and the lack of a mutation on the other allele of the same gene in a subject (e.g., one mutant allele and one wild type allele for a given gene).
• a “heterozygous mutation” can be a “compound heterozygous” mutation, which refers to the presence of a mutation (e.g., loss of function mutation or partial loss of function mutation) on one allele for a given gene and a different (e.g., loss of function mutation or partial loss of function mutation) on the other allele for the same gene (e.g., two different alleles that are both mutated, e.g., non-functional or partially functional).
• the genotype can be a null genotype or functionally deficient genotype.
• homozygous refers to the presence of two identical alleles for a given gene.
• a “homozygous mutation” refers to the presence of two mutant alleles for a given gene, where the two mutant alleles are identical.
• nucleic acid genotype refers to the presence of two non-functional alleles of a gene in a subject.
• unit dosage form refers to a physically discrete unit suited as unitary doses for a subject to be treated. Each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• a dosage refers to a quantity or amount of a therapeutic agent.
• a dosage is the amount administered to the subject in a single administration, e.g., in a single injection, a single infusion, or single administration of one or more unit dosages.
• a dosage is the amount administered to the subject in multiple administrations, e.g., multiple injections, multiple infusions, or multiple administrations of one or more unit dosages.
• a dosage can refer to the total amount administered to the subject in a certain time period, e.g., per day. In such examples, the dosage is typically referred to as “daily dosage” or dosage in terms of quantity per day.
• the hunger or hunger level of a subject can be quantified by using a scale to obtain a hunger score.
• the scale for hunger assigns a higher score for a subject that more frequently (e.g., often or always) feels unbearable hunger and a lower score for a subject that less frequently (e.g., sometimes or never) feels unbearable hunger. See, e.g., Sibilia. Psychological Topics 19 (2010), 2, 341-354.
• a Likert scale for hunger can be used that assigns scores from 1 to 4 points, where a subject who never feels unbearable hunger is assigned a score of 1, where a subject who sometimes feels unbearable hunger is assigned a score of 2, where a subject who often feels unbearable hunger is assigned a score of 3, and where a subject who always feels unbearable hunger is assigned a score of 4. See Id..
• C 1 -C 6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 - C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 alkyl.
• the compounds useful for practicing the methods described herein may possess one or more chiral centers and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present disclosure. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilizing methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the disclosure. The compounds useful for practicing the methods described herein may also comprise one or more isotopic substitutions.
• H may be in any isotopic form, including 'H, 2 H (D or deuterium), and 3 H (T or tritium); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
• pharmaceutically acceptable salt as used herein is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
• base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
• pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
• acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
• Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
• inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
• salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)).
• Certain specific compounds used in the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
• These salts may be prepared by methods known to those skilled in the art.
• Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for use in the present disclosure.
• the compounds useful for practicing the methods described herein can also exist in unsolvated forms as well as solvated forms, including hydrated forms.
• the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure.
• the compounds useful for practicing the methods described herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
• solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
• Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
• the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
• hydrate refers to a compound which is associated with water.
• the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R ⁇ x H 2 O, wherein R is the compound and wherein x is a number greater than 0.
• tautomer refers to compounds that are interchangeable forms of a compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of it electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
• Tyr or Y Tyrosine D-(Et) Tyr has a structure of
• DIEA diisopropylethyl amine
• Dmab 4- ⁇ N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl)- amino ⁇ benzyl
• TIS triisopropylsilane
• TFFH tetramethylfluoroforamidiaium hexafluorophosphate
• N-terminal amino acid For the N-terminal amino acid, the abbreviation stands for the structure of: The designation “NH 2 ” in e.g., as in Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH 2 (SEQ ID NO: 13), indicates that the C-terminus of the peptide is amidated.
• Hydantoin-(C(O)-(A a -A b )) denotes the structure: , wherein amino acid “A a ” has the structure: and amino acid “A b ” the structure:
• a 4 -Cys]- would have the following the structure: whereas a compound represented as “c[Hydantoin(C(O)-(A b -Cys))-A 1 -A 2 -A 3 -A 4 -
• c[Hydantoin(C(O)-(Asp-A b ))-A 1 -A 2 -A 3 -A 4 -Lys]- represents the following compound: whereas “c[Hydantoin(C(O)-(Dap-A b ))-A 1 -A 2 -A 3 -A 4 -Asp]-” has the following formula:
• Acyl refers to R"-C(O)-, where R" is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alklyaryl, and is indicated in the general formula of a particular embodiment as “Ac”.
• Alkyl refers to a hydrocarbon group containing one or more carbon atoms, where multiple carbon atoms if present are joined by single bonds.
• the alkyl hydrocarbon group may be straight-chain or contain one or more branches or cyclic groups.
• Hydroalkyl refers to an alkyl group wherein one or more hydrogen atoms of the hydrocarbon group are substituted with one or more hydroxy radicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like.
• “Substituted alkyl” refers to an alkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, amine (e.g., -NH 2 , -NHCH 2 ), -NO 2 , guanidine, urea, amidine, and -C 1-20 alkyl, wherein said -C 1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, — CF 3 , — OCH 3 , — OCF 3 , and -(CH 2 ) 0-20 -COOH.
• halogen i.e., fluorine, chlorine, bromine, and iodine
• -OH e.g., fluorine
• substituents are present.
• the presence of -(CH 2 ) 0-20 -COOH results in the production of an alkyl acid.
• alkyl acids containing, or consisting of, -(CH 2 ) 0-20 -COOH include 2-norbornane acetic acid, tert-butyric acid, 3 -cyclopentyl propionic acid, and the like.
• halo encompasses fluoro, chloro, bromo and iodo.
• the central bond within this group is an imine, and the group is related structurally to amidines and ureas.
• Heteroalkyl refers to an alkyl wherein one of more of the carbon atoms in the hydrocarbon group is replaced with one or more of the following groups: amino, amido, — O — , — S — or carbonyl. In different embodiments 1 or 2 heteroatoms are present.
• “Substituted heteroalkyl” refers to a heteroalkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine, and iodine), -OH, — CN, — SH, — NH 2 , — NHCH 3 , —NO 2 , and -C 1-20 alkyl, wherein said -C 1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, — CF 3 , -OCH 3 , -OCF 3 , and -(CH 2 ) 0-20 -COOH. In different embodiments 1, 2, 3 or 4 substituents are present.
• halogen i.e., fluorine, chlorine, bromine, and iodine
• Alkenyl refers to a hydrocarbon group made up of two or more carbons where one or more carbon-carbon double bonds are present.
• the alkenyl hydrocarbon group may be straight-chain or contain one or more branches or cyclic groups.
• Substituted alkenyl refers to an alkenyl wherein one or more hydrogens are replaced with one or more substituents selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine, and iodine), — OH, — CN, — SH, — NH 2 , — NHCH 3 , — NO 2 , and — C 1-20 alkyl, wherein said — C 1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, — CF 3 , — OCH 3 , — OCF 3 , and — (CH 2 ) 0-20 — COOH.
• halogen i.e., fluorine, chlorine, bromine, and iodine
• Aryl refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to three conjugated or fused ring systems.
• Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups.
• the aryl is a 5- or 6-membered ring.
• Preferred atoms for a heterocyclic aryl are one or more sulfur, oxygen, and/or nitrogen.
• Non-limiting examples of aryl include phenyl, 1 -naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, 9-anthracene, and the like.
• Aryl substituents are selected from the group consisting of — C 1-20 alkyl, — C 1-20 alkoxy, halogen (i.e., fluorine, chlorine, bromine, and iodine), — OH, — CN, — SH, — NH 2 , -NO 2 , — C 1-20 alkyl substituted with halogens, — CF 3 , — OCF 3 , and — (CH 2 ) 0-20 — COOH.
• the aryl contains 0, 1, 2, 3, or 4 substituents.
• Alkylaryl refers to an “alkyl” joined to an “aryl”.
• (C 1- 12 )hydrocarbon moiety encompasses alkyl, alkenyl and alkynyl and in the case of alkenyl and alkynyl there is C 2 -C 12 .
• substituted means substituted by one or more defined groups.
• groups may be selected from a number of alternative groups, the selected groups may be the same or different.
• the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
• Designation “(amino acid) n ” means that an amino acid is repeated n times.
• designation “(Pro) 2 ” or “(Arg) 3 '' mean that proline or arginine residues are repeated, respectively, two or three times.
• MC4R hMC4R is a protein encoded by a genomic sequence having GenBank accession number CH471077.2. Mutations in the MC4R receptor are an associated cause of severe childhood obesity. The carrier prevalence for MC4R mutations in a juvenile-onset obese population has been noted to be around 2.5% with a highest prevalence of 6% among severely obese children. Humans with MC4R mutations show a more or less similar phenotype as has been described for mice with mutations in the MC4R gene. MC4R deficient patients show hyperphagia, hyperinsulinaemia, increased fat mass, accompanied by lean body mass, bone mineral density and linear growth rate increases, with no changes in cortisol levels, gonadotropin, thyroid and sex steroid levels.
• hyperphagia and hyperinsulinaemia tends to subside with age in human subjects. Similar to the MC4R knockout mice, the phenotype in heterozygote carriers is intermediate in comparison to homozygote carriers. The exhibited hyperphagia observed upon a test meal is less severe than that observed in people with a leptin deficiency. The severity of MC4R dysfunction seen in assays in vitro can predict the amount of food ingested at a test meal by the subject harboring that particular mutation and correlates with the onset and severity of the obese phenotype. At least 90 different MC4R mutations have been associated with obesity and additional mutations in the MC4R are likely to be discovered, leading to a similar obesity phenotype.
• Additional mutations that potentially cause obesity in humans include, R18H, R18L, S36Y, P48S, V50M, F51L, E61K, I69T, D90N, S94R, G98R, I121T, A154D, Y157S, W174C, G181D, F202L, A219 V, I226T, G231S, G238D, N240S, C271R, S295P, P299L, E308K, 1317V, L325F, and 750DelGA, as described in Xiang et al., “Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti -related protein antagonist.” Biochemistry, 2010 Jun 8; 49(22):4583-600, the relevant portions of which are incorporated herein by reference.
• Representative examples include 4-BP DEL, NT631; 4-BP INS, NT732; TYR35TER; ASP37VAL; SER58CYS; ILE102SER; ASN274SER; 1-BP INS, 112A; 4-BP DEL, 211CTCT; ILE125LYS; ALA175THR; ILE316SER; TYR287TER; ASN97ASP; 15-BP DEL (delta88- 92 codons); and SER127LEU.
• the relevant portions of the OMIM database are incorporated herein by reference. Additional exemplary mutations in MC4R are described in Lee. Annals Acad. Med. 38.1(2009):34-44.
• the MC4R mutation results in retention of the MC4R signaling activity.
• Mutations in the genomic sequence encoding MC4R can be detected by the methods that are known to a person of ordinary skill in the art.
• the genomic sequence can be cloned using nucleotide primers, such as e.g, the primers described in Farooqi et al., The Journal of Clinical Investigation, July 2000, vol. 106 (2), pp. 271-279 and Vaisse et al., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 253-262, and the cloned sequence analyzed using commercially available sequencers and software.
• Activity of MC4R can be measured by the methods known to a person of ordinary skill in the art.
• cells can be transiently transfected with the cloned MC4R DNA, the transfected cells contacted by an agonist of MC4R (e.g a- MSH), and the intracellular level of cAMP, the secondary messenger of MC4R, measured by an electrochemiluminescence assay described, e.g., in Roubert et al., Journal of Endocrinology (2010) 207, pp. 177-183.
• a reduction in MC4R signaling can be ascertained by comparing the intracellular level of cAMP produced in response to a given agonist by a wild type MC4R to that produced by a mutant MC4R.
• M4R Melanocortin-4 Receptor
• the melanocortin system which includes melanocortins (MCs), agouti, agouti -related proteins, and their receptors, integrate hormonal, metabolic, and neural signals in order to control energy homeostasis and regulate appetite, energy expenditure, and body weight.
• the MCs which include alpha-melanocyte- stimulating hormone (a-MSH), ⁇ -MSH, ⁇ -MSH, and ACTH, are a family of peptide hormones that are derived from a precursor protein called pro-opiomelanocortin (POMC).
• POMC pro-opiomelanocortin
• Activation of MC4 receptor (MC4R) in the POMC-MC4R pathway increases energy expenditure and decreases food intake. See, e.g., Fan et al.
• the POMC-MC4R pathway includes a number of proteins, such as melanocortins (MCs), MC4 receptor (MC4R), POMC, Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1, also called PC1/3), MAGE-like-2 (MAGEL2), leptin receptor (leptin-R), leptin, 5 -hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix loop helix 2 (NhHL2, also called NSCL2), pro-hormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Siml), that together contribute to the regulation of energy homeostasis, e.g., by regulating appetite and energy expenditure.
• MCs melanocortins
• M4R MC4 receptor
• POMC Proprotein Convertase Subtilisin/Kexin Type 1
• MC4R and other components of the POMC-MC4R pathway have a significant role in weight regulation.
• a mutation of the MC4R gene was reported to result in early-onset and severe obesity. It is believed that other genetic defects in the P0MC-MC4R pathway likely also lead to early-onset and severe obesity.
• These genes are collectively termed “MC4R pathway agonizable genes” and examples are provided below.
• the MC4R pathway agonizable gene does not comprise any one of POMC, Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1, also called PC1/3), MAGE-like-2 (MAGEL2), leptin receptor (leptin-R), leptin, 5 -hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix loop helix 2 (NhHL2, also called NSCL2), pro-hormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Siml).
• the MC4R pathway agonizable gene does not comprise MC4R.
• the MC4R pathway agonizable gene does not comprise any gene disclosed in W02013/102047 or WO 2017/059076, the full contents of each of which is incorporated herein by reference in its entirety.
• ADP Ribosylation Factor-like GTPase 6 (ARL6)
• ADP Ribosylation Factor-like GTPase 6 also known as BBS3, is a member of the ARF-like (ADP ribosylation factor-like) sub-family of the ARF family of GTP -binding proteins, which are involved in the regulation of intracellular traffic.
• ARL6 is involved in membrane protein trafficking at the base of the ciliary organelle and mediates recruitment onto plasma membrane of the BBSome complex. Together with BBS1, ARL6 is necessary for correct trafficking of PKD1 to primary cilia. Together with the BBSome complex and LTZL1, ARL6 controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation.
• SHH sonic hedgehog
• ARL6 may regulate cilia assembly and disassembly and subsequent ciliary signaling events such as the Wnt signaling cascade.
• ARL6 isoform 2 may be required for proper retinal function and organization.
• a vision-specific transcript, encoding long isoform BBS3L, has also been described. Mutations in the ARL6 gene are associated with Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder.
• BBS Bardet-Biedl syndrome
• BBS Bardet-Biedl syndrome
• the human ARL6 gene sequence is provided in GenBank Accession No.
• NG 008119.2 incorporated herein by reference.
• An exemplary human ARL6 nucleic acid sequence is provided in GenBank Accession No. NM_001278293.3, incorporated herein by reference.
• An exemplary amino acid sequence of human ARL6 is provided by Q9H0F7, incorporated herein by reference.
• Retinoic Acid Induced 1 (RAI1)
• Retinoic Acid Induced 1 is a transcription factor that regulates the circadian clock components: CLOCK, ARNTL/BMAL1, ARNTL2/BMAL2, PER1/3, CRY1/2, NR IDI/2, and RORA/C.
• RAI1 positively regulates the transcriptional activity of CLOCK, a core component of the circadian clock.
• CLOCK a transcription factor that regulates the circadian clock components
• ARNTL/BMAL1 ARNTL2/BMAL2
• PER1/3, CRY1/2 NR IDI/2
• RORA/C RORA/C Retinoic Acid Induced 1
• RAI1 positively regulates the transcriptional activity of CLOCK, a core component of the circadian clock.
• RAI1 also regulates transcription through chromatin remodeling by interacting with other proteins in chromatin as well as proteins in the basic transcriptional machinery. It is believed that RAH may be important for embryonic and postnatal development and may be involved in neuronal differentiation.
• RAI1 e.g., leading to haploinsufficiency
• Smith- Magenis Syndrome a disorder characterized by cognitive and behavioral abnormalities, including self-injurious behaviors and sleep disturbance, obesity, and distinct craniofacial and skeletal anomalies, that has been associated with deletions involving chromosome 17pl 1.2.
• Slager et al. Nat Genet. 33(4):466-468 (2003) See, e.g., Slager et al. Nat Genet. 33(4):466-468 (2003).
• the human RAI1 gene sequence is provided in GenBank Accession No.
• SRC1 Steroid Receptor Coactivator 1
• SRC1 Steroid Receptor Coactivator 1
• NCOA1 Nuclear Receptor Coactivator 1
• SRC1 is a transcriptional coactivator for steroid and nuclear hormone receptors.
• SRC1 is a member of the pl60/SRC family, and like other family members, has histone acetyltransferase activity and contains a nuclear localization signal, as well as bHLH and PAS domains.
• SRC1 binds nuclear receptors directly and stimulates the transcriptional activities in a hormone-dependent fashion.
• SRC1 is involved in the coactivation of different nuclear receptors, such as for steroids, retinoids, thyroid hormone, and prostanoids.
• SRC1 is also involved in coactivation mediated by STAT3, STAT5A, STAT5B, and STAT6 transcription factors.
• SRC1 plays a central role in creating multi-subunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. It is required with NCOA2 to control energy balance between white and brown adipose tissues and for mediating steroid hormone response. Alternatively spliced transcript variants encoding different isoforms have also been identified.
• SRC1 has been linked to obesity. Without wishing to be bound by theory, it is believed that SRC-1 modulates the function of hypothalamic Pro- opiomelanocortin (Pome) neurons, which regulate food intake and body weight. Rare heterozygous variants of SRC1 were found in severely obese individuals that impaired leptin mediated Pome reporter activity in cells. (See, e.g., Yang et al. Nat. Commun. 10(1): 1718 (2019)).
• Pome Pro- opiomelanocortin
• the human SRC1 gene sequence is provided in GenBank Accession No.
• NG 029014.2 incorporated herein by reference.
• An exemplary human SRC1 nucleic acid sequence is provided in GenBank Accession No. NM_003743.5, incorporated herein by reference.
• An exemplary amino acid sequence of human SRC1 is provided by QI 5788-1, incorporated herein by reference.
• Bardet-Biedl Syndrome 19 (BBS19), also known as intraflagellar transport protein 27 homolog (IFT27), is a small GTPase-like component of the intraflagellar transport complex B, which is essential for cilia biogenesis and maintenance.
• BBS19 promotes the exit of the BBSome complex from cilia via its interaction with ARL6.
• BBS19 forms a subcomplex within the IFT complex B with IFT25 and prevents aggregation of GTP-free ARL6 but is not believed to be involved in entry of the BBSome complex into cilium. (See, e.g., Liew et al. Dev. Cell 31(3):265-278 (2014)).
• BBS19 is also required for hedgehog signaling.
• BBS19 is essential for male fertility, spermiogenesis and sperm flagella formation, plays a role in the early development of the kidney, and may be involved in the regulation of ureteric bud initiation.
• the human BBS19 gene sequence is provided in GenBank Accession No.
• NG 034205.1 incorporated herein by reference.
• An exemplary human BBS19 nucleic acid sequence is provided in GenBank Accession No. NM_001177701.3, incorporated herein by reference.
• An exemplary amino acid sequence of human BBS19 is provided by Q9BW83-1, incorporated herein by reference.
• the Bardet-Biedl syndrome 21 (BBS21) gene also known as chromosome 8 open reading frame 37 (C8orf37), encodes a broadly expressed protein of unknown function. High levels of BBS21 mRNA can be found in the brain, heart, and retina. The protein has been shown to co-localize with polyglutamyl ated tubulin at the base of the primary cilium in human retinal pigment epithelial cells. Mutations in the BBS21 gene have been associated with Bardet-Biedl syndrome, autosomal recessive cone-rod dystrophy (arCRD), and retinitis pigmentosa (See, e.g., Heon et al. Hum. Mol. Genet. 25(11):2283-2294 (2016)).
• arCRD autosomal recessive cone-rod dystrophy
• retinitis pigmentosa See, e.g., Heon et al. Hum. Mol. Genet. 25(11):2283-2294 (2016)).
• the human BBS21 gene sequence is provided in GenBank Accession No.
• NG 032804.1 incorporated herein by reference.
• An exemplary human BBS21 nucleic acid sequence is provided in GenBank Accession No. NM_177965.4, incorporated herein by reference.
• An exemplary amino acid sequence of human BBS21 is provided by Q96NL8-1, incorporated herein by reference.
• Centrosomal Protein 290 (CEP 290)
• Centrosomal Protein 290 also known as BBS 14 encodes a protein with thirteen putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains, and an ATP/GTP binding site motif A.
• the protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation.
• CEP290 is involved in early and late steps in cilia formation and its association with CCP110 is required for inhibition of primary cilia formation by CCP110.
• CEP290 may play a role in early ciliogenesis in the disappearance of centriolar satellites and in the transition of primary ciliar vesicles (PC V s) to capped ciliary vesicles (CCVs).
• CEP290 is also required for the centrosomal recruitment of RAB8A and for the targeting of centriole satellite proteins to centrosomes such as of PCM1. It is required for the correct localization of ciliary and phototransduction proteins in retinal photoreceptor cells and may play a role in ciliary transport processes. Required for efficient recruitment of RAB8A to primary' cilium.
• CEP290 is part of the tectonic-like complex, which is required for tissue-specific ciliogenesis and may regulate ciliary' membrane composition.
• CEP290 is involved in regulation of the BBSome complex integrity, specifically for presence of BBS2, BBSS, and BBS8/TTC8 in the complex, and in ciliary targeting of selected BBSome cargos.
• CEP290 may play a role in controlling entry of the BBSome complex to cilia.
• ciliopathies including Bardet-Biedl syndrome, isolated retinal degeneration, nephronophthisis (NPHP), Joubert syndrome, Senior-Loken syndrome (SLSN), and neonatal lethal Meckel-Gruber syndrome (MKS).
• NPHP nephronophthisis
• SLSN Senior-Loken syndrome
• MKS neonatal lethal Meckel-Gruber syndrome
• the human CEP290 gene sequence is provided in GenBank Accession No.
• NG 008417.2 incorporated herein by reference.
• An exemplary human CEP290 nucleic acid sequence is provided in GenBank Accession No. NM_025114.4, incorporated herein by reference.
• An exemplary amino acid sequence of human CEP290 is provided by 015078-1, incorporated herein by reference.
• IFT74 Intraflagellar Transport 74
• IFT74 Intraflagellar Transport 74
• IFT74 is a core component of the intraflagellar transport (IFT), a multi-protein complex involved in the transport of ciliary proteins along axonemal microtubules. IFT proteins are found at the base of the cilium as well as inside the cilium, where they assemble into long arrays between the ciliary base and tip. Specifically, IFT74, together with IFT81, forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium. IFT74 binds beta-tubulin via its basic region and is required for ciliogenesis.
• Naturally occurring mutations in this gene are associated with Bardet-Biedl Syndrome and amyotrophic lateral sclerosis— frontotemporal dementia. (See, e.g., Lindstrand et al. Am. J. Hum. Genet. 99(2):318-336 (2016)).
• the human IFT74 gene sequence is provided in GenBank Accession No.
• NG 053083.1 incorporated herein by reference.
• An exemplary human IFT74 nucleic acid sequence is provided in GenBank Accession No. NM_001099222.2, incorporated herein by reference.
• An exemplary amino acid sequence of human IFT74 is provided by Q96LB3-1, incorporated herein by reference.
• LZTFL1 Leucine Zipper Transcription Factor Like 1
• BBS17 Bardet-Biedl Syndrome
• SHH sonic hedgehog
• Nonsense mutations in this gene are associated with a form of Bardet-Biedl Syndrome.
• LZTFL1 may also function as a tumor suppressor; possibly by interacting with E-cadherin and the actin cytoskeleton and thereby regulating the transition of epithelial cells to mesenchymal cells.
• Alternative splicing of LZTFL1 results in multiple transcript variants.
• the human LZTFL1 gene sequence is provided in GenBank Accession No.
• MKS1 MKS Transition Zone Complex Subunit 1
• MKS Transition Zone Complex Subunit 1 (MKS1), also known as BBS13, is a component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
• MKS1 localizes to the basal body and is involved in centrosome migration to the apical cell surface during early ciliogenesis, is required for formation of the primary cilium in ciliated epithelial cells, and is required for ciliary structure and function, including a role in regulating length and appropriate number through modulating centrosome duplication. MKS1 is also required for cell branching morphology.
• the human MKS1 gene sequence is provided in GenBank Accession No.
• NG 013032.1 incorporated herein by reference.
• An exemplary human MKS 1 nucleic acid sequence is provided in GenBank Accession No. NM_017777.4, incorporated herein by reference.
• An exemplary amino acid sequence of human MKS1 is provided by Q9NXB0-1, incorporated herein by reference.
• Tripartite Motif Containing 32 (TRIM32)
• Tripartite Motif Containing 32 also known as BBS11, is a member of the tripartite motif (TRIM) family.
• the protein encoded by the TRIM32 gene contains three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region.
• the protein encoded by TRIM32 localizes to cytoplasmic bodies and to the nucleus, where it interacts with the activation domain of the HIV-1 Tat protein.
• the TRIM32 protein also has E3 ubiquitin ligase activity and has been shown to ubiquitinate DTNBP1 (dysbindin) and promotes its degradation. It may also ubiquitinate BBS2.
• TRIM32 Mutations in TRIM32 have been associated with muscular dystrophy, limb-girdle, autosomal recessive 8, and Bardet-Biedl syndrome (See, e.g., Chiang et al. Proc. Natl. Acad. Sci. U.S.A. 103(16):3287-92 (2006)).
• the human TRIM32 gene sequence is provided in GenBank Accession No.
• TRIM32 nucleic acid sequence is provided in GenBank Accession No. NM_012210.4, incorporated herein by reference.
• An exemplary amino acid sequence of human TRIM32 is provided by Q13049-1, incorporated herein by reference.
• WDPCP Planar Cell Polarity Effector
• WDPCP Planar Cell Polarity Effector
• BBS 15 a cytoplasmic WD40 repeat protein.
• WDPCP is proposed to act as a planar cell polarity protein, which plays a critical role in collective cell movement and ciliogenesis by mediating septin localization.
• WDPCP is proposed to function as core component of the CPLANE (ciliogenesis and planar polarity effectors) complex involved in the recruitment of peripheral IFT-A proteins to basal bodies.
• CPLANE ciliogenesis and planar polarity effectors
• the human WDPCP gene sequence is provided in GenBank Accession No. NG 028144.2, incorporated herein by reference.
• An exemplary human WDPCP nucleic acid sequence is provided in GenBank Accession No. NM_001042692.3, incorporated herein by reference.
• An exemplary amino acid sequence of human WDPCP is provided by 095876-1, incorporated herein by reference.
• Ribosomal Protein S6 Kinase A3 is a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases that acts downstream of ERK (MAPK1/ERK2 and M APK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81, and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1.
• RSK Ribosomal S6 kinase
• RPS6KA3 is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at Ser-lOflwhich results in the subsequent transcriptional activation of several immediate-early genes.
• EGF and PMA mitogenic stimulation
• RPS6KA3 phosphorylates and activates NR4 A 1/NUR77 and ETVI/ER8I transcription factors and the cofactor CREBBP.
• NR4 A 1/NUR77 and ETVI/ER8I transcription factors Upon insulin-derived signal, RPS6KA3 acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at Ser-9 Bind inhibiting its activity.
• RPS6KA3 also phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex.
• RPS6KA3 phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation.
• RPS6KA3 is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at Ser- 1798 y Iwhich potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORCl activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway.
• RPS6KA3 mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function.
• RPS6KA3 promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CC14).
• RPS6KA3 is also involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression.
• RPS6KA3 In LPS-stimulated dendritic cells, RPS6KA3 is involved in TLR4 ⁇ induced macropinocytosis, and in myeloma cells, it acts as effector of FGFR3 -mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3. RPS6KA3 negatively regulates EGF -induced MAPK1/3 phosphorylation via phosphorylation of SOS 1. RPS6KA3 phosphorylates SOS1 at Ser-1134 and Ser-1161 Lihat create YWHAB and YWHAE binding sites and which contribute to the negative regulation of MAPK 1/3 phosphorylation and phosphorylates EPHA2 at Ser-897 ,the RPS6KA-EPHA2 signaling pathway controls cell migration.
• CLS Coffin-Lowry syndrome
• the human RPS6KA3 gene sequence is provided in GenBank Accession No. NG 007488.1, incorporated herein by reference.
• An exemplary human RPS6KA3 nucleic acid sequence is provided in GenBank Accession No. NM 004586.3, incorporated herein by reference.
• An exemplary amino acid sequence of human RPS6KA3 is provided by P51812- 1, incorporated herein by reference.
• HTR2C 5 -Hydroxytryptamine Receptor 2C
• HTR2C is a seven-transmembrane G-protein- coupled receptor for 5-hydroxytryptamine (serotonin). HTR2C also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,- dimethoxy-4-iodophenyl-2-aminopropane (DOI) and lysergic acid diethylamide (LSD).
• DOI dimethoxy-4-iodophenyl-2-aminopropane
• LSD lysergic acid diethylamide
• Ligand binding causes a conformational change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors.
• G proteins guanine nucleotide-binding proteins
• Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3 -kinase and down- stream signaling cascades and promotes the release of Ca 2+ ions from intracellular stores. HTR2C also regulates neuronal activity via the activation of short transient receptor potential calcium channels in the brain, and thereby modulates the activation of pro-opiomelacortin neurons and the release of CRH that then regulates the release of corticosterone. HTR2C plays a role in the regulation of appetite and eating behavior, responses to anxiogenic stimuli and stress, and also plays a role in insulin sensitivity and glucose homeostasis.
• RNA editing events where adenosine residues encoded by the genome are converted to inosines.
• RNA editing is predicted to alter the structure of the second intracellular loop, thereby generating alternate protein forms with decreased ability to interact with G proteins.
• Abnormalities in RNA editing of HTR2C have been detected in victims of suicide that suffer from depression.
• naturally occurring variation in the promoter and 5 non-coding and coding regions of HTR2C may show statistically significant association with mental illness and behavioral disorders.
• Alternative splicing results in multiple different transcript variants. Mutations in HTR2C have been linked to hyperphagia, hyperactivity, and obesity. (See, e.g., Xu et al. Neuron. 60(4):582-9 (2008)).
• the human HTR2C gene sequence is provided in GenBank Accession No.
• KSR2 Kinase Suppressor ofRas 2
• KSR2 Kinase Suppressor ofRas 2
• KSR2 is an intracellular scaffolding protein involved in multiple signaling pathways.
• KSR2 is a location-regulated scaffold connecting MEK to RAF.
• KSR2 has been shown to have very low protein kinase activity and can phosphorylate MAP2K1 at several Ser and Thr residues with very low efficiency in vitro.
• KSR2 Interaction with BRAF enhances KSR2 -mediated phosphorylation of MA.P2K.1 in vitro.
• KSR2 also acts as a negative regulator of MAP3K3 -mediated activation of ERK, INK and NF-kappa-B pathways, inhibiting MAP3K3 -mediated interleukin-8 production.
• KSR2 is an important regulator of energy intake, energy expenditure, and substrate utilization in humans.
• Pearce et al. Cell. 155(4):765-77 (2013) See, e.g., Pearce et al. Cell. 155(4):765-77 (2013).
• the human KSR2 gene sequence is provided within GenBank Accession No. NC_000012.12, incorporated herein by reference.
• An exemplary human KSR2 nucleic acid sequence is provided in GenBank Accession No. NM 173598.6, incorporated herein by reference.
• An exemplary amino acid sequence of human KSR2 is provided by Q6VAB6-1, incorporated herein by reference.
• the prokineticin 2 (PROK2) gene encodes a protein expressed in the suprachiasmatic nucleus (SCN) circadian clock that may function as the output component of the circadian clock.
• the secreted form of the encoded protein may also serve as a chemoattractant for neuronal precursor cells in the olfactory bulb.
• Proteins from other vertebrates which are similar to the PROK2 gene product were isolated based on homology to snake venom; secretions from frog skin and have been shown to have diverse functions.
• PROK2 Mutations in PROK2 are associated with hypogonadotropic hypogonadism 4 with or without anosmia and Kallmann syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. (See, e.g., Dode et al. PLoS Genet. 2(10):el75 (2006)).
• the human PROK2 gene sequence is provided in GenBank Accession No. NG 008275.1, incorporated herein by reference.
• An exemplary human PROK2 nucleic acid sequence is provided in GenBank Accession No. NM_001126128.2, incorporated herein by reference.
• An exemplary amino acid sequence of human PROK2 is provided by Q9HC23-1, incorporated herein by reference.
• Ras-Related Protein Rab-23 is a small GTPase of the Ras superfamily.
• the small GTPases Rab are involved in the regulation of diverse cellular functions associated with intracellular membrane trafficking, including autophagy and immune response to bacterial infection. Rabs cycle between an inactive GDP -bound form and an active GIF- bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering, and fusion.
• the protein encoded by RAB23 prevents nuclear import of GLI1, and thereby inhibits GL11 transcription factor activity.
• RAB23 also regulates GLI1 in differentiating chondrocytes, regulates GL.I3 proteolytic processing, and modulates GLI2 and GLI3 transcription factor activity.
• RAB23 also plays a role in autophagic vacuole assembly, and mediates defense against pathogens, such as S. aureus, by promoting their capture by autophagosomes that then merge with lysosomes.
• RAB23 may play a role in central nervous system development by antagonizing sonic hedgehog signaling.
• RAB23 Mutations in RAB23 have been associated with cancer and Carpenter syndrome, a pleiotropic disorder with autosomal recessive inheritance, the cardinal features of which include craniosynostosis, polysyndactyly, obesity, and cardiac defects. (See, e.g., Jenkins et al. Am. J. Hum. Genet. 80(6): 1162-70 (2007)). Alternative splicing results in multiple transcript variants.
• the human RAB23 gene sequence is provided in GenBank Accession No. NG 012170.1, incorporated herein by reference.
• An exemplary human RAB23 nucleic acid sequence is provided in GenBank Accession No. NM_016277.5, incorporated herein by reference.
• An exemplary amino acid sequence of human RAB23 is provided by Q9ULC3-1, incorporated herein by reference.
• MRAP2 Melanocortin 2 Receptor Accessory Protein 2
• MRAP2 is a G-protein-coupled receptor accessory protein that modulates melanocortin receptor signaling and is involved in energy homeostasis.
• the encoded protein has been shown to interact with all known melanocortin receptors and may regulate both receptor trafficking and activation in response to ligands.
• MRAP2 is thought to play a central role in the control of energy homeostasis and body weight regulation by increasing ligand-sensitivity of MC4R and MC4R-mediated generation of cAMP.
• MRAP2 may also act as a negative regulator of MC2R (e.g., by competing with MRAP for binding to MC2R and impairs the binding of corticotropin (ACTH) to MC2R). MRAP2 may also regulate activity of other melanocortin receptors (MC1R, MC3R and MC5R). MRAP2 has been implicated in energy control in rodents, notably via the melanocortin -4 receptor.
• MRAP2 Deficiencies in MRAP2 have been associated with obesity (e.g., monogenic hyperphagic obesity, hyperglycemia, and hypertension) in both children and adults. (See, e.g., Baron et al. Nat. Med. 25(11): 1733-1738 (2019)).
• the human MRAP2 gene sequence is provided in GenBank Accession No. NG_051944.1, incorporated herein by reference.
• An exemplary human MRAP2 nucleic acid sequence is provided in GenBank Accession No. NM_138409.4, incorporated herein by reference.
• An exemplary amino acid sequence of human MRAP2 is provided by Q96G30-1, incorporated herein by reference.
• AFF4 AF4/FMR2 family member 4
• P-TEFb positive transcription elongation factor b
• SEC super elongation complex
• AFF4 acts as a central scaffold that recruits other factors through direct interactions with ELL proteins (e.g., ELL, ELL2, or ELL3) and the P-TEFb complex.
• ELL proteins e.g., ELL, ELL2, or ELL3
• the SEC complex is recruited by the viral Tat protein to stimulate viral gene expression.
• ATF4 Chromosomal aberrations involving ATF4 have been found in acute lymphoblastic leukemia (ALL). Missense mutations in AFF4 have been associated with CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia). (See, e.g., Izumi et al. Nat. Genet. 47(4):338-44 (2015)).
• the human AFF4 gene sequence is provided in GenBank Accession No.
• NG 030340.1 incorporated herein by reference.
• An exemplary human AFF4 nucleic acid sequence is provided in GenBank Accession No. NM_014423.4, incorporated herein by reference.
• An exemplary amino acid sequence of human AFF4 is provided by Q9UHB7-1, incorporated herein by reference.
• ADCY3 Adenylate Cyclase 3
• ADCY3 Adenylate cyclase 3
• cAMP secondary messenger cyclic adenosine monophosphate
• ADCY3 catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling and participates in signaling cascades triggered by odorant receptors via its function in cAMP biosynthesis.
• ADCY3 is required for the perception of odorants, for normal sperm motility, and normal male fertility.
• ADCY3 also plays a role in regulating insulin levels and body fat accumulation in response to a high fat diet.
• ADCY3 is widely expressed in various human tissues and may be involved in a number of physiological and pathophysiological metabolic processes. Two transcript variants encoding different isoforms have been identified for ADCY3.
• ADCY4 Loss of function mutations in ADCY4 have been associated with monogenic severe obesity. (See, e.g., Saeed et al. Nat. Genet. 50(2): 175-179 (2016)).
• the human ADCY3 gene sequence is provided within GenBank Accession No. NC_000002.12, incorporated herein by reference.
• An exemplary human ADCY3 nucleic acid sequence is provided in GenBank Accession No. NM_001320613.2, incorporated herein by reference.
• An exemplary amino acid sequence of human ADCY3 is provided by 060266- 1, incorporated herein by reference.
• TUB Bipartite Transcription Factor TUB Bipartite Transcription Factor
• TUB Bipartite Transcription Factor is a member of the Tubby family of bipartite transcription factors that functions in signal transduction from heterotrimeric G protein-coupled receptors. The crystal structure has been determined for a similar protein in mouse, which functions as a membrane-bound transcription regulator that translocates to the nucleus in response to phosphoinositide hydrolysis. TUB binds to membranes containing phosphatidylinositol 4, 5 -bisphosphate and has been shown to bind DNA in vitro. TUB may contribute to the regulation of transcription in the nucleus and could be involved in the hypothalamic regulation of body weight. TUB contributes to stimulation of phagocytosis of apoptotic retinal pigment epithelium (RPE) cells and macrophages. Two transcript variants encoding distinct isoforms have been identified for this gene.
• RPE retinal pigment epithelium
• the human TUB gene sequence is provided in GenBank Accession No.
• NG 029912.1 incorporated herein by reference.
• An exemplary human TUB nucleic acid sequence is provided in GenBank Accession No. NM_003320.4, incorporated herein by reference.
• An exemplary amino acid sequence of human TUB is provided by P50607-1, incorporated herein by reference.
• OTP Orthopedia Homeobox
• HD family proteins are helix-turn-helix transcription factors that play key roles in the specification of cell fates. OTP may function during brain development, specifically in the differentiation of hypothalamic neuroendocrine cells. OTP is also believed to be involved in mammalian energy homeostasis and behavior.
• the human OTP gene sequence is provided within GenBank Accession No.
• GPR101 G-Protein Coupled Receptor 101
• G-Protein Coupled Receptor 101 is an orphan G protein -coupled receptor of largely unknown function.
• the encoded protein is a member of a family of proteins that contain seven transmembrane domains and transduce extracellular signals through heterotrimeric G proteins.
• GPR101 Diseases associated with GPR101 include Pituitary' Adenoma 2, Growth Hormone- Secreting and Chromosome Xq26.3 Duplication Syndrome. Neuronal GLP1Rs has been shown to mediate body weight and anorectic effects of liraglutide but are not required for glucose-lowering effects. (See, e.g., Sisley et al. J. Clin. Invest. 124(6):2456-63 (2014)).
• the human GPR101 gene sequence is provided in GenBank Accession No.
• NG 016367.1 incorporated herein by reference.
• An exemplary human GPR101 nucleic acid sequence is provided in GenBank Accession No. NM_054021.2, incorporated herein by reference.
• An exemplary amino acid sequence of human GPR101 is provided by Q96P66-1, incorporated herein by reference.
• T-Box Transcription Factor 3 (TBX3)
• T-Box Transcription Factor 3 is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box.
• T-box genes encode transcription factors involved in the regulation of developmental processes.
• TBX3 is a transcriptional repressor and is thought to play a role in the anterior/posterior axis of the tetrapod forelimb.
• TBX3 acts as a negative regulator of PML function in cellular senescence.
• TBX3 may also play a role in limb pattern formation. Alternative splicing of this gene results in three transcript variants encoding different isoforms.
• UMS Ulnar-mammary syndrome
• the human TBX3 gene sequence is provided in GenBank Accession No.
• the method comprises treating a subject having a mutation in a gene listed in Table 1 below.
• a method described herein comprises use of a MC4R agonist described herein to treat a subject having a mutation in an MC4R pathway agonizable gene, e.g., as listed in Table 1.
• Table 1 describes exemplary genes, alleles, transcripts, and proteins, though other genes, alleles, transcripts, and proteins may be included.
• Table 1 Exemplary MC4R pathway agonizable genes, alleles, and transcripts
• ACBD7 Acyl-CoA Binding Domain Containing 7
• BA455B2.2 Acyl-CoA Binding Domain Containing 7
• AGRP Agouti Related Neuropeptide
• CARM1 Cell Adhesion Molecule 1
• CARM2 Cell Adhesion Molecule 2
• IGSF4D IGSF4D
• CARTPT Cocaine and Amphetamine-Regulated Transcript Protein (CARTPT), also known as CART, has been associated with obesity. (See, e.g., Asnicar et al. Endocrinology. 42(10):4394-400 (2001)).
• CCDC28B Coiled-Coil Domain Containing 28B
• Cholecystokinin also known as Prepro-Cholecystokinin, has been associated with obesity and body mass index. (See, e.g., Namjou et al. Front. Genet. 3;4:268 (2013)).
• Cannabinoid Receptor 1 also known as CNR
• CNR1 has been associated with obesity and body fat mass and distribution.
• CREBBP CREB Binding Protein
• RSTS CREB Binding Protein
• CREB3 Regulatory Factor also known as C5orf41, has been associated with obesity and diabetes. (See, e.g., Hanson et al. Diabetologia. 62(9): 1647-1652 (2019)).
• Cullin 4B also known as KIAA0695, MRXHF2, MRXS15, MRXSC, and SFM2
• Cullin 4B has been associated with mental retardation, X-linked, syndromic 15 (Cabezas type).
• Cabezas type See, e.g., Tarpey et al. Am. J. Hum. Genet. 80(2):345-52 (2007)).
• DNA Methyltransferase 3 Alpha also known as HESJAS and TBRS, encodes a protein involved in de novo methylation. (See, e.g., Xie S. et al. Gene 236(1):87- 95 (1999)).
• Dual Specificity Tyrosine Phosphorylation Regulated Kinase IB also known as Minibrain-related kinase, has been associated with abdominal obesity-metabolic syndrome 3.
• DYRK1B Dual Specificity Tyrosine Phosphorylation Regulated Kinase IB
• Minibrain-related kinase has been associated with abdominal obesity-metabolic syndrome 3.
• Keramati et al. N. Engl. J. Med. 15;370(20): 1909-1919 (2014) See, e.g., Keramati et al. N. Engl. J. Med. 15;370(20): 1909-1919 (2014).
• Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1), also known as NPPS, M6S1, and PDNP1, has been associated with obesity. (See, e.g., Valli-Jaakola et al. Obesity. 16(9):2113-9 (2008)).
• EP300 also known as Histone Acetyltransferase P300, has been associated with Rubinstein-Taybi syndrome. (See, e.g., Stevens et al. Am. J. Med. Genet. A. 155A(7):1680-4 (2011)).
• FMRP Translational Regulator 1 also known as POF1 and POF
• FMRI FMRP Translational Regulator 1
• POF1 and POF have been associated with Fragile X Syndrome.
• FTO Alpha-Ketoglutarate Dependent Dioxygenase also known as FTO Alpha-Ketoglutarate Dependent Dioxygenase
• FTO Alpha-Ketoglutarate Dependent Dioxygenase has been associated with obesity-related traits including body mass index, hip circumference, and weight.
• Ghrelin and Obestatin Prepropeptide also known as Prepro-Appetite Regulatory Hormone, has been associated with obesity. (See, e.g., J. Clin. Endocrinol. Metab. 87(8):4005-8 (2002)).
• GIP-R and PGQTL2 Gastric Inhibitory Polypeptide Receptor
• GLP1R Glucagon Like Peptide 1 Receptor
• Inositol Polyphosphate-5 -Phosphatase E also known as JBTS1
• JBTS1 Inositol Polyphosphate-5 -Phosphatase E
• Insulin also known as IDDM2 and IDDM1
• IDDM2 Insulin
• Insulin Induced Gene 2 also known as Insulin Induced Protein 2
• INSIG2 Insulin Induced Gene 2
• Insulin Receptor Substrate 1 also known as HIRS-1, has been associated with obesity, type II diabetes, and susceptibility to insulin resistance. (See, e.g., Clausen et al. Lancet. 346(8972):397-402 (1995)).
• Insulin Receptor Substrate 4 also known as Ppi 60, CHNG9, PY160, and Pyl60, has been associated with obesity, hyperglycemia, and insulin resistance. (See, e.g., Sadagurski et al. Mol. Metab. 23 ;3(1):55-63 (2013)).
• Insulin Gene Enhancer Protein also known as Islet-1 and Isl-1, is a member of the LIM/homeodomain family of transcription factors, and mutations in this gene have been associated with, inter alia, maturity-onset diabetes. (See, e.g., Tanizawa Y et al. Diabetes (1994)).
• Methyl-CpG Binding Protein 2 (MeCP2), also known as AUTSX3, MRXS13, MRX16, RTS, and RTT, encodes a nuclear protein related to onset of Rett syndrome, a progressive neurologic developmental disorder.
• Methyl-CpG Binding Protein 2 (MeCP2), also known as AUTSX3, MRXS13, MRX16, RTS, and RTT, encodes a nuclear protein related to onset of Rett syndrome, a progressive neurologic developmental disorder. Amir, R.E. et al. Nat Genet 23(2): 185-8 (1999)
• Neuropilin 1 also known as CD304 and BDCA4, encodes one of two neuropilins involved in signaling pathways that control cell migration. NRP1 is associated with cerebral arteriopathy, autosomal dominant, and neuroma. (See, e.g., Soker, S. et al Cell 92(6):735-745).
• NPN2 Neuropilin 2
• NP2 neuropilin 2
• PRO2714 may play a role in cardiovascular development, axon guidance, and tumorigenesis.
• RPGRIP1L also known as FTM, PPP1R134, CORS3, MKS5, JBTS7, and KIAA1005, has been found to interact with neprocystin-4. Defects in this gene have been associated with Joubert syndrome type 7 and Meckel syndrome type 5 (Nagase, T et al DNA Res 6(l):63-70 (1999)).
• Plexin Al (PLXNA1), also known as NOV and PLXN1, is associated with hereditary congenital facial paresis and nephronophthisis 4. (See, e.g., Maestrini, E. et al. Proc Natl Acad Sci USA 93(2):674-678 (1996)).
• Plexin A2 (PLXNA2), also known as OCT, KIAA0463, and FLJ11751, is a plexin-A family member believed to be related to signal transduction from semaphorin-3 A and semaphorin-3B. (See, e.g., also Coric, V. et al. Depress Anxiety 27(5):417-425 (2010)).
• Plexin A3 (PLXNA3), also known as XAP-6, is involved in cytoskeletal remodeling and apoptosis. This gene has been shown to be important in axon pathfinding in developing nervous systems and is associated with tumor progression. (See, e.g., Maestrini, L. et al. Proc Natl Acad Sci USA 93(2):674-678 (1996)).
• Plexin A4 also known as FAYV2820, KIAA1550, and PR034003, is associated with various signal transduction pathways, particularly involving semaphorin-3 A and semaphorin-3 B. (See, e.g., Imboden, M. J Allergy Clin Immunol 129(5): 1218-1228 (2012)).
• KIDINS220 Kinase D Interacting Substrate 220
• ARMS KIAA1250
• SINO Kinase D Interacting Substrate 220
• MCHR1 Melanin Concentrating Hormone Receptor 1
• GPR24 Melanin Concentrating Hormone Receptor 1
• MSRA Methionine Sulfoxide Reductase A
• Necdin, MAGE Family Member also known as PWCR, has been associated with Prader-Willi syndrome. (See, e.g., Jay et al. Nat. Genet. 17(3):357-61 (1997)).
• Neuronal Growth Regulator 1 also known as Neurotractin, IGLON4, DMML2433, KILON, and Ntra, has been associated with body mass index. (See, e.g., Zhao et al. Obesity. 17(12):2254-7 (2009)).
• Neuroligin 2 (NLGN2), also known as KIAA1366, has been associated with anxiety, autism, intellectual disability, hyperphagia, and obesity. (See, e.g., Am. J. Med. Genet. A. 173(1):213-216 (2017)).
• Neuropeptide Y also known as PYY4, has been associated with obesity. (See, e.g., van Rossum et al. Int. J. Obes. 30(10): 1522-8 (2006)).
• Nuclear Receptor Subfamily 0 Group B Member 2 (NR0B2), also known as SHP1, has been associated with mild and early-onset obesity. (See, e.g., Nishigori et al. PNAS. 16;98(2):575-80 (2001)).
• NTRK2 Neurotrophic Receptor Tyrosine Kinase 2
• Trk-B Neurotrophic Receptor Tyrosine Kinase 2
• Opioid Receptor Mu 1 also known as MORI, MOP, LMOR, OPRM, and HMOP
• OPRM1 Opioid Receptor Mu 1
• PCNT Pericentrin
• Pleckstrin Homology Domain Interacting Protein also known as WDR11, Ndrp, DCAF14, BRWD2.
• PCSK2 Proprotein Convertase Subtilisin/Kexin Type 2
• NEC2 Proprotein Convertase Subtilisin/Kexin Type 2
• PHD Finger Protein 6 also known as BFLS and BORJ
• PHA6 PHD Finger Protein 6
• Börjeson-Forssman-Lehman syndrome a syndrome characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of subcutaneous tissue of the face, narrow palpebral fissure, and large but not deformed ears.
• PMCH Pro-Melanin Concentrating Hormone
• Peroxisome Proliferator Activated Receptor Gamma also known as NR1C3, PPARG1, PPARG2, CIMT1, and GLM1 has been associated with obesity in children and adolescents.
• PPAG Peroxisome Proliferator Activated Receptor Gamma
• Peptide YY also known as Peptide Tyrosine Tyrosine
• PYY Peptide Tyrosine Tyrosine
• Syndecan 3 also known as SDCN, has been associated with energy balance, obesity, body mass index, and LHDL cholesterol. (See, e.g., Chang et al. Int. J. Endocrinol. 30;2018:9282598 (2016)).
• SNRPN Small Nuclear Ribonucleoprotein Polypeptide N
• PWCR Small Nuclear Ribonucleoprotein Polypeptide N
• Thyroid Hormone Receptor Beta also known as ERBA2 and PRTH, has been associated with regulation of food intake and body weight. (See e.g., Amorim et al. J. Endocrinol. 203(2):291-9 (2009)).
• TRPC5 Transient Receptor Potential Cation Channel Subfamily C Member 5
• PPP1R159 also known as PPP1R159
• TRP-5 Transient Receptor Potential Cation Channel Subfamily C Member 5
• HTRP5 Transient Receptor Potential Cation Channel Subfamily C Member 5
• Transmembrane Protein 18 also known as LncND, has been associated with body mass index and body weight regulation. (See, e.g., Wilier et al. Nat. Genet. 41(l):25-34 (2009)).
• Transmembrane Protein 67 also known as MKS3, has been associated with Bardet-Biedl Syndrome. (See, e.g., Leitch et al. Nat. Genet. 40(4):443-8 (2008)).
• Trafficking Protein Particle Complex 9 also known as NIBP, has been associated with mental retardation, autosomal recessive 13. (See, e.g., Marangi et al. Eur. J. Hum. Genet. 21(2):229-32 (2013)).
• Uncoupling Protein 1 also known as thermogenin, SLC25A7, and UCP, has been associated with obesity. (See, e.g., Ramos et al. BMC Med. Genet. 7;13:101 (2012)).
• Uncoupling Protein 3 also known as SLC25A9, has been associated with metabolic fuel partitioning and obesity. (See, e.g., Argyropoulos et al. J. Clin. Invest. 1; 102(7): 1345-51 (1998)).
• Vacuolar Protein Sorting 13 Homolog B also known as CHS1 and COH1
• Cohen syndrome an autosomal recessive disorder with variability in the clinical manifestations, characterized by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia.
• the MC4R pathway agonizable gene comprises POMC, PCSK1, LEPR, LEP, SDCCAG8, SH2B1, CPE, ALMS1, BBS1, BBS2, BBS4, BBS5, BBS6, BBS7, BBS8, BBS9, BBS10, BBS12, BBS18, BBS20, GNAS, MC3R, NHLH2, SIM1, BDNF, NTRK2, MAGEL2, or a 16pl 1.2 deletion.
• the present disclosure features methods for treating a subject having a disease, disorder, or condition relating to an MC4R pathway agonizable gene.
• the disease, disorder, or condition is characterized by a mutation (e.g., a substitution mutation, a deletion mutation, or a polymorphism) in the MC4R pathway agonizable gene.
• the methods comprise administering to the subject an MC4R agonist or compositions described herein, e.g., a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), (e.g., as described herein) or a pharmaceutically acceptable salt thereof.
• the MC4R agonist is setmelanotide (i.e., Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 (SEQ ID NO: 140))
• a MC4R agonist e.g., MC4R agonist described herein, e.g., setmelanotide
• MC4R pathway agonizable gene is selected from ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMRI, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG
• a MC4R agonist e.g., MC4R agonist described herein, e.g., setmelanotide
• MC4R pathway agonizable gene is selected from ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMRI, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG
• the genetic disorder is associated with obesity, e.g., severe obesity, and/or hyperphagia.
• the genetic disorder is BBS.
• the genetic disorder is Alström syndrome.
• the genetic disorder is Smith-Magenis syndrome.
• the genetic disorder is hypothalamic obesity.
• a MC4R agonist described herein is used to treat Bardet- Biedl syndrome (BBS).
• BBS is a genetically heterogeneous disorder.
• BBS is a form of Laurence-Moon-Beidl syndrome and is characterized by obesity, retinopathy, learning disability, polydactyly, and hypogenitalism. See, e.g., Green et al. New Engl. J. Med. 321(1989): 1002-9.
• BBS is characterized by one or more mutation(s) in one or more of 20 genes (BBS 1 -BBS20). Most of the BBS genes encode proteins thought to be important for the function, formation, and stability of cilia.
• BBS1 BBS2, BBS4, BBS5, BBS7, BBS8, BBS9, and BBS18
• BBS6, BBS 10, and BBS 12 are believed to form a complex with the CCT/TRiC family of group II chaperonins. Mutation(s) in the BBS gene(s) are thought to lead to defective cilia, e.g, neuronal cilia, or dysfunctional ciliary regulation. Ciliary dysfunction is believed to cause impaired leptin signaling and hyperleptinemia.
• BBS mutant mice for example, is thought to be caused by leptin resistance and defects in leptin receptor trafficking. See, e.g., Berbari et al. Proc. Natl. Acad. Sci. USA 110.19(2013):7796- 7801. BBS2, BB4, and BB6 mutant mice have been shown to be hyperleptinemic and failed to reduce their food intake in response to leptin. See, e.g., Berbari et al. Proc. Natl. Acad. Sci. USA 110.19(2013):7796-7801.
• Alström syndrome Alström syndrome is an autosomal recessive disease with clinical symptoms that include severe obesity, hyperinsulinemia, and altered glucose metabolism that can lead to the development of type 2 diabetes at a young age in afflicted subjects.
• ALMS is caused by mutations in A MS1, a gene that has been mapped to chormosome 2pl3.
• PWS Prader Willi Syndrome
• PWS Prader Willi Syndrome
• a hallmark of PWS is severe hyperphagia — an overriding physiological drive to eat — leading to severe obesity and other complications.
• Obesity is one of the greatest health threats to PWS patients, and hyperphagia impairs the ability of PWS patients to live independently, requiring costly and constant supervision to prevent overeating. Without supervision, these patients are likely to die prematurely as a result of choking, stomach rupture, or from complications caused by morbid obesity.
• Symptoms of PWS include infantile hypotonia with failure to thrive, rapid weight gain and overeating during childhood, as well as intellectual disability, developmental delay, short stature, hypogonadism. Diagnostic criteria for PWS are described, e.g., in Holm et al. Pediatrics 91(1993):398-402.
• the genetics underlying PWS involve a loss of function of several genes on chromosome 15 in humans, in particular, at 15q11-q13. See, e.g., Schaaf et al. Nat. Genet. 45.11(2013): 1405-09.
• the MC4R agonists described herein e.g., setmelanotide
• the melanocortin receptor agonists described herein, e.g., setmelanotide can act as a replacement therapy for MSH.
• Smith-Magenis syndrome is a neurob ehavi oral disorder characterized by a recognizable pattern of physical, behavioral, and developmental features. Common features of the disease include hypotonia, poor gross motor and fine motor skills, feeding problems in infancy, speech delay, developmental delay, intellectual disability, scoliosis, short fingers and toes, vision problems, middle ear abnormalities, sleep disturbances, hearing impairment, decreased sensitivity to pain, and constipation. It is a rare disorder, occurring in between 1 out of every 15,000 to 25,000 individuals. Smith-Magenis syndrome is caused by mutations in the gene RAI 1, in particular on chromosomal region 17p 11.2. While Smith-Magenis syndrome disease is genetic, it is often not familial, and often not inherited from either parent (see, e.g., Falco et al. Appl Clin Genet (2017) 10:85-94).
• Hypothalamic obesity is a form of obesity caused by physical or inherited damage to the hypothalamus, resulting in symptoms such as uncontrollable hunger, rapid and/or excessive weight gain, and a low metabolic rate.
• causes for this condition include the presence of a tumor, swelling in the brain, head trauma, radiotherapy, brain surgery, or the presence of certain genetic mutations.
• hypothalamic obesity may be caused by craniopharyngioma, a rare non-cancerous tumor. Removal of this tumor can result in damage to the hypothalamus, leading to symptoms of hypothalamic obesity.
• Additional diseases, disorders, or conditions that may be treated by administration of an MC4R agonist or compositions described herein, e.g., a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), (e.g, as described herein) or a pharmaceutically acceptable salt thereof include 5p3 microduplication syndrome, Angelman syndrome, Chudley Lowry syndrome, Cornelia de Lange syndrome, Laron syndrome, Kleefstra syndrome/9q34.3, Camera-Marugo-Cohen syndrome, Clark and Baraitser XLMR syndrome, DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, 22ql 1.2 deletion syndrome, rapid onset obesity with hypothalamic dysfunction (ROHHAD), rapid onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neural crest tumor (ROHHAD NET), Shashi XLMR
• an MC4R agonist e.g., an MC4R agonist described herein, include those summarized in Kaur et al (2017) Obesity Reviews 18:603- 634. Outcomes
• methods described herein result in one or more outcomes, including a reduction of weight (e.g., body weight), a reduction in hunger level, no detectable decrease in energy expenditure (e.g., resting energy expenditure), an increase in energy expenditure (e.g., resting energy expenditure), a reduction in daily/weekly/monthly food intake, a reduction in waist circumference, no detectable increase in blood pressure, or a reduction in blood pressure in a subject, e.g., relative to a control.
• weight e.g., body weight
• a reduction in hunger level e.g., no detectable decrease in energy expenditure (e.g., resting energy expenditure)
• an increase in energy expenditure e.g., resting energy expenditure
• a reduction in daily/weekly/monthly food intake e.g., a reduction in waist circumference
• no detectable increase in blood pressure e.g., relative to a control.
• control is the measurement of the parameter in the subject prior to administration of (treatment with) a MC4R agonist.
• the control is a predetermined value, e.g., the value of the parameter in an average obese human population, e.g., of like age and gender as the subject; or the value of the parameter measured in the subject at a previous time point (e.g., at a previous visit, e.g., to a physician, medical facility or laboratory).
• the outcome (e.g., the reduction, increase, no detectable decrease, or no detectable increase in a given parameter) is measured in the subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment with a MC4R agonist.
• the outcome e.g., the reduction, increase, no detectable decrease, or no detectable increase in a given parameter
• is measured in the subject over a period of time e.g., over a period of 1-2 weeks, 2-4 weeks, 4-6 weeks, 6-8 weeks, 8-12 weeks, or 12-16 weeks
• methods described herein result in a reduction of weight (e.g., body weight) in the subject compared to a control (e.g., weight of the subject before treatment or a predetermined value, e.g., average weight of an obese human population of like age and gender as the subject not subjected to therapeutic intervention, or the weight of the subject at a previous measurement, e.g., at a previous visit).
• the reduction is about 1 kg to 3 kg after 1 week of treatment, about 1 kg to 6 kg after 2 weeks of treatment, about 2 kg to 12 kg after 4 weeks of treatment, about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment.
• the reduction is at a rate of loss of about 1-2 kg/week, e.g., about 2 kg/week, e.g., over a period of 1-2 weeks of treatment or longer, 2-4 weeks of treatment or longer, 4-8 weeks of treatment or longer, 8-16 weeks of treatment, or 16-32 weeks of treatment, or longer.
• Measurement of weight e.g., body weight
• Measurement of weight can be performed using standard methods in the art.
• methods described herein result in a reduction in hunger level in the subject compared to a control (e.g., hunger level of the subject before treatment or a predetermined hunger level, e.g., average hunger level of an obese human population of like age and gender as the subject or the hunger level of the subject at a previous measurement, e.g., at a previous visit).
• a control e.g., hunger level of the subject before treatment or a predetermined hunger level, e.g., average hunger level of an obese human population of like age and gender as the subject or the hunger level of the subject at a previous measurement, e.g., at a previous visit.
• the methods described herein result in abolishment of hunger in the subject.
• hunger is measured by a scale, such as a Likert hunger scale, which ranges from 0 to 10 and is described herein.
• methods described herein result in a reduction in hunger score in the subject compared to a control (e.g., hunger level of the subject before treatment or a predetermined hunger level, e.g., average hunger level of an obese human population of like age and gender as the subject or the hunger level of the subject at a previous measurement, e.g., at a previous visit).
• methods described herein result in a lower score on the Likert hunger scale, e.g., a lower score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 points, compared to the control (e.g., hunger level of the subject before treatment or a predetermined hunger level, e.g., average hunger level of an obese human population of like age and gender as the subject or the hunger level of the subject at a previous measurement, e.g., at a previous visit).
• methods described herein result in a score of 0 on the Likert hunger scale after treatment.
• the reduction in hunger level is measured/ob served after 1 to 2 weeks of treatment or longer, 2-4 weeks of treatment or longer, 4-8 weeks of treatment or longer, or 8-16 weeks of treatment or longer.
• REE is a measure of the basal metabolic rate of the subject and can be determined using methods such as those described in Chen et al. J. Clin. Endocrinol. Metab. 100.4(2015): 1639-45.
• the REE can be determined by placing the subject in a whole-room indirect calorimeter (also called a metabolic chamber) at a certain time after treatment (e.g., after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks).
• the REE is measured in 30-minute measurements periods, and in some cases, REE values from several 30-minute periods are averaged to generate an average REE.
• the REE can be determined after a 10-12 hour fasting period, at thermoneutrality (e.g., around 25 deg C), where the subject is awake without psychological or physical stress.
• REE is measured in units of energy per unit time (e.g., kcal/h or kcal/day).
• the REE is measured relative to kg lean body mass in a subject (e.g., REE/kg lean mass), e.g., as described in the Examples.
• methods described herein result in no change or no decrease in energy expenditure, e.g., resting energy expenditure (REE), in the subject over an hourly, daily (e.g., in 24 hours), weekly (e.g., in 7 days), or monthly (e.g., in 30 days) period compared to a control REE (e.g., the REE in the subject prior to treatment or a predetermined REE, e.g., average REE of an obese human population of like age and gender and normalized for weight as the subject or the REE of the subject at a previous measurement, e.g., previous visit), e.g., as measured after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment.
• REE resting energy expenditure
• methods described herein result in no detectable change or no detectable decrease in energy expenditure, e.g., resting energy expenditure (REE) per kg lean body mass, in the subject over an hourly, daily (e.g., in 24 hours), weekly (e.g., in 7 days), or monthly (e.g., in 30 days) period compared to the control REE (e.g., the REE in the subject prior to treatment or a predetermined REE, e.g., average REE of an obese human population of like age and gender as the subject or the REE of the subject at a previous measurement, e.g., previous visit), e.g., as measured after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment.
• REE resting energy expenditure
• methods described herein result in an increase in energy expenditure, e.g., resting energy expenditure (REE), in the subject over a hourly, daily (e.g., in 24 hours), weekly (e.g., in 7 days), or monthly (e.g., in 30 days) period compared to a control REE (e.g., the REE in the subject prior to treatment or a predetermined REE, e.g., average REE of an obese human population of like age and gender and normalized for weight as the subject or the REE of the subject at a previous measurement, e.g., previous visit), e.g., as measured after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment.
• REE resting energy expenditure
• the increase in REE in the subject is at least 20 kcal/day (e.g., at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150 kcal/day or more), e.g., as measured after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment.
• the increase in REE in the subject is at least 2% (e.g., at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or more), e.g., as measured after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment, compared to the REE in the subject prior to treatment.
• the REE in the subject (e.g., adult subject) after treatment with a MC4R agonist is at least 1800 kcal/day (e.g., at least 1800, 1825, 1850, 1875, 1900, 1925, 1950, 1975, 2000, 2025, 2050, 2100, 2150, 2200, 2250, 2300, 2400 kcal/day, or more), e.g., for an adult subject.
• the REE in the subject (e.g., pediatric subject) after treatment with a MC4R agonist is at least 200 kcal/day (e.g., at least 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500 kcal/day or more), e.g., for pediatric patients.
• methods described herein result in a reduction in food intake by the subject compared to a control (e.g., the food intake of the subject prior to treatment or a predetermined food intake level, e.g., the food intake of an average human obese population or the food intake of the subject at a previous measurement, e.g., at a previous visit), e.g., where the food intake is measured as daily food intake or food intake over a period of 24 hours, or one week,.
• a control e.g., the food intake of the subject prior to treatment or a predetermined food intake level, e.g., the food intake of an average human obese population or the food intake of the subject at a previous measurement, e.g., at a previous visit
• the food intake is measured as daily food intake or food intake over a period of 24 hours, or one week,.
• the reduction is at least 100 kilocalories, e.g., at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 1000 kilocalories or more, e.g., for daily food intake or food intake over a period of 24 hours, or one week, or 30 days or for longer time periods, e.g., for an adult subject.
• mean food intake can decrease from a baseline at or above about 100 kcal/kg/day to about 90, 80, 70, 60, 50, 40, 30, 20 or 10 kcal/kg/day or lower after treatment with a MC4R agonist, e.g., setmelanotide, e.g., in a pediatric subject at about 1 year of age.
• mean food intake can decrease from a baseline at or above about 40 kcal/kg/day to about 35, 30, 20 or 10 kcal/kg/day or lower after treatment with a MC4R agonist, e.g., setmelanotide, e.g., in a pediatric subject in late adolescence.
• Food intake can be determined by standard methods, e.g., as described in Rutishauser. Pub. Health Nutr. 8.7A(2005): 1100-07.
• methods described herein result in a reduction in waist circumference of the subject compared to a control (e.g., the waist circumference of the subject prior to treatment or the waist circumference of the subject at a previous measurement, e.g., previous visit), as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.
• a control e.g., the waist circumference of the subject prior to treatment or the waist circumference of the subject at a previous measurement, e.g., previous visit
• the reduction in waist circumference is at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm or more) in the subject (e.g., adult subject) compared to a control (e.g., the waist circumference of the subject prior to treatment or a predetermined waist circumference, e.g., the waist circumference of an average obese human population of like age and gender or the waist circumference of the subject at a previous measurement, e.g., previous visit), as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.
• a control e.g., the waist circumference of the subject prior to treatment or a predetermined waist circumference, e.g., the waist circumference of an average obese human population of like age and gender or the waist circumference of the subject at a previous measurement, e.g., previous visit
• the waist circumference is measured using standard methods. In embodiments, the waist circumference is the largest circumference around a subject’s mid-section, e.g., around a subject’s abdomen. In other embodiments, the waist circumference is measured around the natural waist (e.g., in between the lowest rib and the top of the hip bone), the umbilicus, or at the narrowest point of the midsection.
• methods described herein result in no detectable increase in blood pressure (e.g., diastolic and/or systolic blood pressure) of the subject compared to a control blood pressure (e.g., the blood pressure of the subject prior to treatment or a predetermined blood pressure, e.g., the blood pressure of an average obese human population of like age and gender or the blood pressure of the subject at a previous measurement, e.g., previous visit), as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.
• a control blood pressure e.g., the blood pressure of the subject prior to treatment or a predetermined blood pressure, e.g., the blood pressure of an average obese human population of like age and gender or the blood pressure of the subject at a previous measurement, e.g., previous visit
• methods described herein result in a reduction in blood pressure (e.g., diastolic and/or systolic blood pressure) of the subject a control blood pressure (e.g., the blood pressure of the subject prior to treatment or a predetermined blood pressure, e.g., the blood pressure of an average obese human population of like age and gender or the blood pressure of the subject at a previous measurement, e.g., previous visit), as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.
• blood pressure e.g., diastolic and/or systolic blood pressure
• a control blood pressure e.g., the blood pressure of the subject prior to treatment or a predetermined blood pressure, e.g., the blood pressure of an average obese human population of like age and gender or the blood pressure of the subject at a previous measurement, e.g., previous visit
• the reduction in blood pressure is at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg or more) compared to the blood pressure of the subject prior to treatment, as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.
• the reduction in blood pressure is at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg or more) compared to the blood pressure of the subject prior to treatment, as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.
• the methods described herein do not result in an adverse effect on heart rate or blood pressure.
• the subject is obese, e.g., prior to administration of an MC4R agonist described herein, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration of the MC4R agonist.
• the subject is a severely obese, pediatric or adult patient e.g., prior to administration of an MC4R agonist described herein, e.g., at the time the MC4R agonist is prescribed or at the time of the first administration of the MC4R agonist.
• the subject is hyperphagic, e.g., prior to administration of an MC4R agonist described herein, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration of the MC4R agonist.
• the subject e.g., adult subject
• BMI body mass index
• the subject e.g., pediatric subject
• BMI body mass index
• the subject has a body weight of at least about 5 kg, e.g., at least about 5 kg, 10 kg, 20kg, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140,145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220 kg or greater, e.g., prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration.
• the subject has a body weight of a least 20 kg, at least 60 kg, or at least 100 kg, e.g., prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration.
• the subject has received intervention in the gastrointestinal system.
• the subject may have received a gallbladder surgery, an intestinal surgery, a gastric surgery (e.g., a bariatric surgery), or other survival procedure.
• the subject has received a gastric bypass surgery.
• the subject has received a surgery resulting in a restriction of the total amount of food capable of being held or processed at one time, e.g., the stomach, small intestine, large intestine, or colon.
• the subject is an adult, e.g., 18 years of age or older, e.g., 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, or older.
• the subject is a pediatric subject, e.g., less 18 years of age or younger (e.g., 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year of age or younger.
• the subject has or is identified as having a defect, e.g., genetic defect, or a mutation, in an MC4R pathway agonizable gene.
• the subject has or is identified as having a mutation a gene selected from n the ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMRI, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG2, IRS1, IRS4, KCTD15, KIDINS220, MC
• methods herein can comprise identifying or selecting a subject having a defect e.g., genetic defect, or a mutation, in one or more genes listed in Table 1. In embodiments, methods herein can comprise acquiring knowledge of the genotype, predetermined sequence, or mutation.
• the methods herein can comprise acquiring knowledge of the genotype of, e.g., of a mutation in one or more of ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMRI, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG2, IRS1, IRS4, KCTD15, KIDINS220, MCHR1, MSRA, NDN, NEGRI, NLGN2, NPY, NR0B2, NTRK2, PCNT
• the MC4R agonist is administered in response to acquiring knowledge, e.g., detection or identification, of a predetermined sequence, e.g., a mutation, in a gene described herein, one or more of ARL6, RAH, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMRI, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG2, IRS1, IRS4, KCTD15, KIDINS220, MCHR1, MSRA, N
• identification or selection of a subject as having a certain genotype or predetermined sequence, e.g., mutation, in a gene can comprise acquiring knowledge of the certain genotype or predetermined sequence, e.g., mutation.
• Knowledge of the sort can be acquired in a number of ways, as described in detail in the Definitions section.
• a sequence is acquired, e.g., by obtaining possession of a nucleotide sequence, by “directly acquiring” or “indirectly acquiring” the sequence.
• Directly acquiring a sequence means performing a process (e.g., performing a synthetic or analytical method) to obtain the sequence, such as performing a sequencing method (e.g., a Next Generation Sequencing (NGS) method).
• NGS Next Generation Sequencing
• Indirectly acquiring a sequence refers to receiving information or knowledge of, or receiving, the sequence from another party or source (e.g., a third-party laboratory that directly acquired the sequence).
• the sequence acquired need not be a full sequence, e.g., sequencing of at least one nucleotide, or obtaining information or knowledge, that identifies a genotype or predetermined sequence, e.g., mutation, disclosed herein as being present in a subject constitutes acquiring a sequence.
• the sequence can be directly acquired.
• Directly acquiring a sequence includes performing a process that includes a physical change in a physical substance, e.g., a starting material, such as a tissue sample, e.g., a blood sample or tissue biopsy, or analysis of an isolated nucleic acid (e.g., DNA or RNA) sample.
• a starting material such as a tissue sample, e.g., a blood sample or tissue biopsy
• an isolated nucleic acid e.g., DNA or RNA
• Exemplary changes include making a physical entity from two or more starting materials, shearing or fragmenting a substance, such as a genomic DNA fragment; separating or purifying a substance (e.g., isolating a nucleic acid sample from a tissue); combining two or more separate entities into a mixture, performing a chemical reaction that includes breaking or forming a covalent or non-covalent bond.
• Directly acquiring a value includes performing a process that includes a physical change in a
• acquiring knowledge of the certain genotype or predetermined sequence, e.g., mutation can comprise acquiring a sample, e.g., from which the genotype or predetermined sequence, e.g., mutation, is determined.
• acquiring a sample refers to obtaining possession of a sample, e.g., a tissue sample or nucleic acid sample, by “directly acquiring” or “indirectly acquiring” the sample.
• Directly acquiring a sample means performing a process (e.g., performing a physical method such as a surgery or extraction) to obtain the sample.
• Directly acquiring a sample refers to receiving the sample from another party or source (e.g., a third-party laboratory that directly acquired the sample).
• Directly acquiring a sample includes performing a process that includes a physical change in a physical substance, e.g., a starting material, such as a tissue, e.g., a tissue in a human patient or a tissue that has was previously isolated from a patient.
• Exemplary changes include making a physical entity from a starting material, dissecting or scraping a tissue; separating or purifying a substance (e.g., a sample tissue or a nucleic acid sample); combining two or more separate entities into a mixture; performing a chemical reaction that includes breaking or forming a covalent or non-covalent bond.
• Directly acquiring a sample includes performing a process that includes a physical change in a sample or another substance, e.g., as described above.
• provided herein is also a method of evaluating a subject, e.g., for likely responsiveness to a MC4R agonist, e.g., a MC4R agonist described herein, e.g., setmelanotide.
• the method comprises acquiring information about the genotype of the subject.
• the method comprises acquiring information about the presence or absence of a defect, e.g., genetic defect, in one or more genes listed in Table 1 in the subject.
• the subject can be identified as having a defect, e.g., genetic defect, e.g., mutation, in one or more genes listed in Table 1, using methods described herein.
• a defect e.g., genetic defect, e.g., mutation
• the identification of the subject having a defect indicates that the subject is likely to respond (e.g., with an improvement in one or more symptoms) to a MC4R agonist, e.g., a MC4R agonist described herein, e.g., setmelanotide.
• a MC4R agonist e.g., a MC4R agonist described herein, e.g., setmelanotide.
• an improvement in a symptom can include an outcome described herein.
• an improvement in a symptom can include a reduction of weight (e.g., body weight), a reduction in hunger level, no detectable decrease in energy expenditure (e.g., resting energy expenditure), an increase in energy expenditure (e.g., resting energy expenditure), a reduction in daily/weekly/monthly food intake, or a reduction in waist circumference, e.g., relative to a control.
• weight e.g., body weight
• a reduction in hunger level e.g., no detectable decrease in energy expenditure
• an increase in energy expenditure e.g., resting energy expenditure
• a reduction in daily/weekly/monthly food intake e.g., a reduction in waist circumference, e.g., relative to a control.
• the identification of the subject having the defect indicates that the subject is more likely to respond to (or is likely to have a greater response to) a MC4R agonist, e.g., a MC4R agonist described herein, e.g., setmelanotide, than a subject (e.g., obese subject, e.g., of like age and/or pre-treatment weight) lacking a genetic defect in one or more genes listed in Table 1, e.g., a wild-type obese subject.
• a MC4R agonist e.g., a MC4R agonist described herein, e.g., setmelanotide
• a subject that is more likely to respond is more likely to have one or more improved symptoms, such as symptoms described herein, e.g., compared to a control, e.g., a subject (e.g., obese subject, e.g., of like age and/or pre-treatment weight) lacking a genetic defect in one or more genes listed in Table 1, e.g., a wild-type obese subject.
• a control e.g., a subject (e.g., obese subject, e.g., of like age and/or pre-treatment weight) lacking a genetic defect in one or more genes listed in Table 1, e.g., a wild-type obese subject.
• a subject that is likely to have a greater response is likely to have a greater improvement in symptoms, e.g., symptoms described herein, e.g., greater weight loss, greater decrease in waist circumference, greater increase in resting energy expenditure, greater decrease in food intake, greater decrease in hunger level, e.g., compared to a control, e.g., a subject (e.g., obese subject, e.g., of like age and/or pre-treatment weight) lacking a genetic defect in one or more genes listed in Table 1, e.g., a wild-type obese subject.
• a control e.g., a subject (e.g., obese subject, e.g., of like age and/or pre-treatment weight) lacking a genetic defect in one or more genes listed in Table 1, e.g., a wild-type obese subject.
• methods described herein further comprise providing a report that identifies the presence or absence of the genetic defect and in some cases an identifier for the subject.
• the report provides a recommendation on potential therapeutic options, likely effectiveness of a therapeutic option, and/or recommendations/instructions for administration of the therapeutic option (e.g., MC4R agonist, e.g., MC4R agonist described herein, e.g., setmelanotide).
• MC4R melanocorin 4 receptor
• MC4R agonists include a-MSH, ⁇ -MSH, y-MSH and adenocorti citropic hormone (ACTH) or a functional fragment thereof.
• ACTH adenocorti citropic hormone
• synthetic MC4R agonists are described in detail below.
• an MC4R agonist can be any known agonist of MC4R.
• the MC4R agonist is not an adrenocorticotropic hormone (ACTH) or a fragment thereof.
• Exemplary MC4R agonists include those described in WO201 1104378; WO2011104379; W0201060901; WO200887189, WO200887188, WO200887187, WO200887186; US20110065652; W02010144341; WO2010144344; WO201065799; W0201065800; W0201065801; W0201065802; W0201037081; W02009152079; WO2009151383; US20100311648; US20100280079; W0201081666; W0201034500; W0200910299; W02008116665; WO201052256; WO201052255; WO201 126015; US20100120783; WO201096854; US20100190793; W0201025142; WO2014144260; W02017059075; and W0201015972.
• MC4R agonists are found in U.S. Pat. No. 8,263,608; U.S. Pat. No. 8,247,530; U.S. Pat. No. 8,114,844; and U.S. Pat. No. 7,968,548. The entire teachings of these publications are incorporated herein by reference.
• the MC4R agonist is a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt thereof as described herein.
• the MC4R agonist is a compound of any one of Formulas (I) or (II), or a pharmaceutically acceptable salt thereof as described herein.
• the MC4R agonist is a compound of Formula (I).
• the MC4R agonist is a compound of Formula (II).
• the agonist of MC4R is a tripeptide D-Phe-Arg-Trp (SEQ ID NO: 560) or a pharmaceutical salt thereof.
• the agonist is any peptide that includes SEQ ID NO: 560 or a pharmaceutical salt thereof.
• the MC4R agonist is an acetylated tripeptide Ac-D-Phe-Arg-Trp-NH 2 (SEQ ID NO: 561) or a pharmaceutical salt thereof.
• the MC4R agonist is a compound of Formula (I): (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 1O -R 1 (I) or a pharmaceutically acceptable salt thereof, wherein A 1 is Acc, HN — (CFFU — C(O), L- or D-amino acid, or deleted; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu; A 3 is Gly, Ala, ⁇ -Ala, Gaba, Aib, D-amino acid, or deleted; A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2- Thi, 3-Thi, or (X 1 , X 2 , X 3 , X 4 , X 5 )Phe; A 5 is D-P
• R 4 when R 4 is (C 1 -C 40 )acyl, aryl(C 1 -C 40 )acyl, substituted (C 1 -C 40 )acyl, substituted aryl(C 1 -C 40 )acyl, (C 1 -C 40 )alkylsulfonyl, or -C(NH)-NH 2 , then R 5 is H or (C 1 -C 40 )alkyl, (C 1 -C 40 )heteroalkyl, (C 2 -C 40 )alkenyl, (C 2 -C 40 )alkynyl, aryl(C 1 -C 40 )alkyl, substituted (C 1 -C 40 )alkyl, substituted (C 1 -C 40 )heteroalkyl, substituted (C 2 - C 40 )alkenyl, substituted (C 2 -C 40 )alkynyl, or substituted aryl
• R 2 is (C 1 -C 30 )acyl, aryl(C 1 -C 30 )acyl, substituted (C 1 -C 30 )acyl, or substituted aryl(C 1 -C 30 )acyl
• R 3 is H, (C 1 -C 30 )alkyl, (C 1 -C 30 )heteroalkyl, (C 2 -C 30 )alkenyl, (C 2 -C 30 )alkynyl, aryl(C 1 -C 30 )alkyl, substituted (C 1 - C 30 )alkyl, substituted (C 1 -C 30 )heteroalkyl, substituted (C 2 -C 30 )alkenyl, substituted (C 2 - C 30 )alkynyl, or substituted aryl(C 1 -C 30 )alkyl;
• a 3 or A 8 or both must be present in said compound.
• a 9 is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen.
• a 9 is Dab, Dap, Orn, or Lys.
• a 8 when A 8 is Ala or Gly, then A 1 is not NIe.
• R 2 and R 3 cannot both be H.
• a 1 is A6c, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, I1e, Leu, hLeu, Met, ⁇ -hMet, 2-Nal, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, Vai, or deleted;
• a 2 is Asp, Cys, D-Cys, hCys, D-hCys, Glu, Pen, or D-Pen;
• a 3 is D-Abu, Aib, Ala, ⁇ -Ala, D-Ala, D-Cha, Gaba, D-Glu, Gly, D-Ile, D-Leu, D-Tle, D-Val, or deleted;A 4 is His or 3-Pal;
• a 5 is D-Bal, D-l-Nal, D-2-Nal, D-Phe, D-Trp, or D
• the compound of Formula (I) is a compound disclosed in International Patent Application Publication Number WO 2007/008704, which is incorporated herein by reference in its entirety.
• the compound of Formula (I) is selected from:
• SEQ ID NO: 8 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH 2 ;
• SEQ ID NO: 10 Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
• SEQ ID NO: 12 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
• SEQ ID NO: 13 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
• SEQ ID NO: 14 Ac-Nle-c(Cys- ⁇ -Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
• SEQ ID NO: 18 Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
• SEQ ID NO: 20 Ac-Nle-c(D-Cys- ⁇ -Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
• SEQ ID NO: 22 Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
• SEQ ID NO: 24 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ;
• SEQ ID NO: 25 Ac-Nle-c(Cys- ⁇ -Ala-His-D-Phe-Arg-Trp-D-Cys)- NH 2 ;
• SEQ ID NO: 26 Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)- NH 2 ;
• SEQ ID NO: 27 Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)- NH 2 ;
• SEQ ID NO: 28 Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ;
• SEQ ID NO: 30 Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)- NH 2 ;
• SEQ ID NO: 32 Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)- NH 2 ;
• SEQ ID NO: 33 Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)- NH 2 ;
• SEQ ID NO: 34 Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)- NH 2 ;
• SEQ ID NO: 36 Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)- NH 2 ;
• SEQ ID NO: 38 Ac-D-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)- NH 2 ;
• SEQ ID NO: 39 Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)- NH 2 ;
• SEQ ID NO: 40 Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)- NH 2 ;
• SEQ ID NO: 42 Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)- NH 2 ;
• SEQ ID NO: 43 Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
• SEQ ID NO: 44 Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)- NH 2 ;
• SEQ ID NO: 46 n-butyryl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)- NH 2 ;
• SEQ ID NO: 48 Ac- ⁇ -hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)- NH 2 ;
• SEQ ID NO: 49 Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)- NH 2 ;
• SEQ ID NO: 50 Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)- NH 2 ;
• SEQ ID NO: 52 Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)- NH 2 ;
• SEQ ID NO: 54 Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)- NH 2 ;
• SEQ ID NO: 55 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)- NH 2 ;
• SEQ ID NO: 56 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp- ⁇ -Ala-Lys)- NH 2 ;
• SEQ ID NO: 58 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)- NH 2 ;
• SEQ ID NO: 64 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)- NH 2 ;
• SEQ ID NO: 65 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)- NH 2 ;
• SEQ ID NO: 70 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)- NH 2 ;
• SEQ ID NO: 74 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)- NH 2 ;
• SEQIDNO: 75 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)- NH 2 ;
• SEQ ID NO: 80 D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp- ⁇ -Ala-D-Cys)-Thr- NH 2 ;
• SEQIDNO: 86 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)- NH 2 ;
• SEQIDNO 90 Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)- NH 2 ;
• SEQIDNO 99 Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)- NH 2 ;
• SEQIDNO 100 Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)- NH 2 ;
• SEQIDNO 101 Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)- NH 2 ;
• SEQIDNO 102 Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)- NH 2 ;
• SEQIDNO 104 Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)- NH 2 ;
• SEQ ID NO: 110 Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp- ⁇ -Ala-Lys)- NH 2 ;
• SEQ ID NO: 140 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH 2 ;
• SEQ ID NO: 147 Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)- NH 2 ; or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I) is Ac-Arg-c(Cys-D-Ala-His-D-Phe- Arg-Trp-Cys)-NH 2 (SEQ ID NO: 140) or a pharmaceutically acceptable salt thereof.
• the MC4R agonist is a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein:
• X 1 is ; X 2 is ; A 1 is Asp, Cys, D-Cys, Dab, Dap, Glu, Lys, Om,
• a 2 is an L- or D-amino acid
• a 3 is H is, 2-Pal, 3-Pal, 4-Pal, (X 1 , X 2 , X 3 , X 4 , X 5 )Phe, Taz, 2-Thi or 3-Thi
• a 4 is D-Bal, D-l-Nal, D-2-Nal, D-Phe or D-(X 1 , X 2 , X 3 , X 4 , X 5 )Phe
• a 5 is Arg, hArg, Dab, Dap, Lys or Orn
• a 6 is Bal, 1-Nal, 2-Nal, (X 1 , X 2 , X 3 , X 4 , X 5 )Phe or Trp
• a 7 is Asp, Cys, D-Cys, Dab, Dap, Glu, Lys, Orn, Pen or D-Pen
• R 1 is H, (C 1 -C 10 )alkyl or
• a 1 is Cys;
• a 2 is D-Ala, Asn, Asp, Gin, Glu or D-Phe;
• a 3 is H is;
• a 4 is D-2-Nal or D-Phe;
• a 5 is Arg;
• a 6 is Trp; and
• a 7 is Cys or Pen;
• each of R', R 2 , R 3 , and R 9 is, independently, H;
• R 4 is C(O)NH 2 ;
• each of R 5 and R 6 is, independently, H, (C 1 -C 10 )heteroalkyl, substituted (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )heteroalkyl or R 5 and R 6 may be fused together form a cyclic moiety; and
• each of R 7 and R 8 is, independently, H, (C 1 -C 10 )alkyl, (C 1 -C 10 )heteroalkyl, substituted (C 1
• the compound of Formula (II) is selected from: (SEQ ID NO: 500)
• the compound of Formula (II) is described in WO2008/147556 or International Patent Application Number PCT/US08/06675, each of which is incorporated herein by reference in its entirety.
• the compound of Formula (II) is hydantoin(C(O)-(Arg-Gly))-c(Cys-
• Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 (SEQ ID NO: 500) or a pharmaceutically acceptable salt thereof, also known as RM-511.
• a pharmaceutically acceptable salt thereof also known as RM-511.
• the structure of hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu- His-D-Phe-Arg-Trp-Cys)-NH 2 (SEQ ID NO: 500) is shown below:
• the MC4R agonist is a compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of — CH 2 — S— S— CH 2 — , -C(CH 3 ) 2 — S— S— CH 2 — , — CH 2 — S— S— C(CH 3 ) 2 — , — C(CH 3 ) 2 — S— S— C(CH 3 ) 2 — , — (CH 2 ) 2 — S— CH 2 — , — CH 2 — S— S— (CH 2 ) 2 -, — (CH 2 ) 2 — S— S— (CH 2 ) 2 — , — C(CH 3 ) 2 — S— S— (CH 2 ) 2 — , — (CH 2 ) 2 — S— C(CH 3 ) 2 — ,
• R 2 each is, independently, H, (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl
• R 3 is — OH or — NH 2
• R 4 and R 5 each is, independently, H, (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl
• X 1 is
• a 1 is H is, 2 -Pal, 3-Pal, 4-Pal, (X 1 , X 2 , X 3 , X 4 , X 5 )Phe, Taz, 2-Thi, 3-Thi or is deleted;
• a 2 is D-Bal, D-l-Nal, D-2-Nal, D-Phe or D-(X 1 , X 2 , X 3 , X 4 , X 5 )Phe;
• a 3 is Arg, hArg, Dab, Dap, Lys or Orn;
• a 4 is Bal, 1-Nal, 2-Nal, (X 1 , X 2 , X 3 , X 4 , X 5 )Phe or Trp;
• R 6 and R 7 each is, independently for each occurrence thereof, H, (C 1 -C 10 )heteroalkyl, aryl(C 1 -C 5 )alkyl, substituted (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )heteroalkyl or substituted aryl(C 1 -C 5 )alkyl provided that R 6 and R 7 may be joined together to form a ring;
• R 8 is H, (C
• the compound of Formula (III) is selected from:
• the MC4R agonist is a compound of Formula (IV):
• R 2 R 3 (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-NH 2 (IV) or a pharmaceutically acceptable salt thereof, wherein A 1 is Nle or deleted; A 2 is Cys or Asp; A 3 is Glu or D-Ala; A 4 is His; A 5 is D-Phe; A 6 is Arg; A 7 is Trp, 2-Nal or Bal; A 8 is Gly, Ala, D-Ala, (3 -Ala, Gaba or Apn; A 9 is Cys or Lys; each of R 2 and R 3 is independently selected from the group consisting of H or (C 1 -C 6 )acyl.
• Exemplary MC4R agonists of Formula (IV) are disclosed in International Patent Application Publication Number WO 2007/008704, which is incorporated herein by reference in its entirety.
• the compound of Formula (IV) is selected from:
• the MC4R agonist is a compound of Formula (V): (R 2 R 3 )-B 1 -A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -A 11 -A 12 -A 13 -B 2 -B 3 -R 1 (V) or a pharmaceutically acceptable salt thereof:
• B 1 is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, wherein at least 5 amino acids are independently selected from the group consisting of L-Arg, D-Arg, L-hArg and D-hArg, or B 1 is optionally deleted;
• a 1 is Acc, HN-(CH 2 ) m -C(O), L- or D-amino acid or deleted;
• a 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu;
• R 4 when R 4 is (C 1 -C 40 )acyl, aryl(C 1 -C 40 )acyl, substituted (C 1 -C 40 )acyl, substituted aryl(C 1 -C 40 )acyl, (C 1 -C 40 )alkylsulfonyl or C(NH) — NH 2 , then R 5 is H, (C 1 -C 40 )alkyl, (C 1 - C 40 )heteroalkyl, (C 2 -C 40 )alkenyl, (C 2 -C 40 )alkynyl, aryl(C 1 -C 40 )alkyl, substituted (C 1 - C 40 )alkyl, substituted (C 1 -C 40 )heteroalkyl, substituted (C 2 -C 40 )alkenyl, substituted (C 2 - C 40 )alkynyl or substituted aryl(C 1 -C 40 )
• R 2 is (C 1 -C 30 )acyl, aryl(C 1 -C 30 )acyl, substituted (C 1 -C 30 )acyl or substituted aryl(C 1 -C 30 )acyl
• R 3 is H, (C 1 -C 30 )alkyl, (C 1 -C 30 )heteroalkyl, (C 2 -C 30 )alkenyl, (C 2 - C 30 )alkynyl, aryl(C 1 -C 30 )alkyl, substituted (C 1 -C 30 )alkyl, substituted (C 1 -C 30 )heteroalkyl, substituted (C 2 -C 30 )alkenyl, substituted (C 2 -C 30 )alkynyl or substituted aryl(C 1 -C 30 )alkyl;
• B 1 nor B 2 contains one or more of the following amino acid sequences: Arg-(Lys)2-(Arg) 2 -Gln-(Arg) 3 , Tyr-Ala-Arg-Lys-Ala-(Arg) 2 -Gln-Ala-(Arg) 2 , Tyr-Ala-Arg- (Ala)2-(Arg) 2 -(Ala)2-(Arg) 2 , Tyr-Ala-(Arg)9, Tyr-(Ala)3-(Arg) 7 , Tyr-Ala-Arg-Ala-Pro- (Arg) 2 -Ala-(Arg) 3 or Tyr-Ala-Arg-Ala-Pro-(Arg) 2 -Pro-(Arg) 2 ;
• B 1 is Arg-Lys-Gln-Lys-(Arg)5, Arg-(Lys)2-Arg-Gln-(Arg)4, Arg-(Lys)2-(Arg) 3 -Gln- (Arg) 2 , Arg-(Lys)2-(Arg) 4 -Gln-Arg, Arg-(Lys)2-(Arg) 5 -Gln, Arg-(Lys)2-Gln-(Arg) 5 , Arg-Gln- (Lys)2-(Arg) 5 , Arg-Gln-(Arg) 7 , Arg-Gln-(Arg) 8 , (Arg) 2 -Gln-(Arg) 6 , (Arg) 2 -Gln-(Arg) 7 , (Arg) 3 -Gln-(Arg) 5 , (Arg) 3 -Gln-(Arg) 6 , (Arg) 4 -Gln-(Arg) 4 , (Arg) 4
• B 2 is ⁇ -Ala, ⁇ -Ala-Gly, ⁇ -Ala-Tyr, ⁇ -Ala-Tyr-Gly, ( ⁇ -Ala) 2 , ( ⁇ -Ala) 2 -Gly, ( ⁇ -Ala) 2 - Tyr, ( ⁇ -Ala) 2 -Tyr-Gly, Doc, Doc-Gly, Doc-Tyr, Doc-Tyr-Gly, (Doc) 2 , (Doc)2-Gly, (Doc) 2 - Tyr, Doc)2-Tyr-Gly, or deleted;
• B 3 is Arg-Lys-Gln-Lys-(Arg) 5 , Arg-Lys-(Arg) 3 -Gln-(Arg) 3 , Arg-(Lys)2-Arg-Gln- (Arg) 4 , Arg-(Lys)2-Gln-(Arg) 5 , Arg-(Lys)2-(Arg) 2 -Gln-(Arg) 3 , Arg-(Lys)2-(Arg) 3 -Gln-(Arg) 2 , Arg-(Lys)2-(Arg) 4 -Gln-Arg, Arg-(Lys)2-(Arg) 5 -Gln, Arg-Gln-(Lys)2-(Arg) 5 , Arg-Gln-(Arg) 7 , Arg-Gln-(Arg) v , (Arg) 2 -Lys-(Arg) 2 -Gln-(Arg) 3 , (Arg) 2
• a 1 is A6c, Cha, hCha, Chg, D-Chg, hChg, Gaba, hLeu, Met, ⁇ -hMet, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, or deleted;
• a 2 is Cys
• a 3 is D-Abu, Aib, Ala, ⁇ -Ala, D-Ala, D-Cha, Gaba, Glu, Gly, D-Ile, D-Leu, D-Met, D-Nle, D-Phe, D-Tle, D-Trp, D-Tyr, D-Val, or deleted;
• a 4 is H
• a 5 is D-Bal, D-l-Nal, D-2-Nal, D-Phe, D-(X 4 , X 2 , X 3 , X 4 , X 5 )Phe, D-Trp, or D- (Et)Tyr;
• a 6 is Arg or hArg
• a 7 is Bal, Bip, 1-Nal, 2-Nal, Trp, or D-Trp;
• a 8 is A5c, A6c, Aha, Ahx, Ala, ⁇ -Ala, Apn, Gaba, Gly, or deleted;
• a 9 is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or D-Pen;
• a 10 is Pro, Thr or deleted
• a 11 is Pro or deleted
• a 12 is arg, Lys, or deleted
• a 13 is Asp or deleted; each of R 2 and R 3 is, independently, H or acyl; or pharmaceutically acceptable salts thereof.
• the compound of Formula (V) is selected from:

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Diabetes (AREA)
• Gastroenterology & Hepatology (AREA)
• Dermatology (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Child & Adolescent Psychology (AREA)
• Immunology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Peptides Or Proteins (AREA)
• Medicines Containing Plant Substances (AREA)
• Cosmetics (AREA)
• Medicinal Preparation (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=80845850

Family Applications (1)

Country Status (13)

Cited By (3)

Citations (2)

Family Cites Families (1)

• 2021
  • 2021-09-24 EP EP21873549.6A patent/EP4216979A4/en active Pending
  • 2021-09-24 TW TW110135665A patent/TW202228760A/zh unknown
  • 2021-09-24 JP JP2023518779A patent/JP2023542985A/ja active Pending
  • 2021-09-24 CA CA3192873A patent/CA3192873A1/en active Pending
  • 2021-09-24 AU AU2021350017A patent/AU2021350017A1/en active Pending
  • 2021-09-24 MX MX2023003360A patent/MX2023003360A/es unknown
  • 2021-09-24 WO PCT/US2021/052032 patent/WO2022067086A1/en not_active Ceased
  • 2021-09-24 US US18/028,117 patent/US20240058414A1/en active Pending
  • 2021-09-24 KR KR1020237013822A patent/KR20230095956A/ko active Pending
  • 2021-09-24 CN CN202180071771.8A patent/CN116507353A/zh active Pending
  • 2021-09-24 AR ARP210102664A patent/AR123603A1/es unknown
• 2022
  • 2022-07-07 CO CONC2022/0009561A patent/CO2022009561A2/es unknown
• 2023
  • 2023-03-22 CL CL2023000823A patent/CL2023000823A1/es unknown

Patent Citations (2)

Non-Patent Citations (4)

Also Published As

Similar Documents

Legal Events