COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY ACCELERATED FIBROSARCOMA POLYPEPTIDES
First Claim
1. A bifunctional compound having the chemical structure:
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ULM-L-PTM,or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,wherein;
the ULM is a small molecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase;
the PTM is a small molecule comprising a rapidly accelerated fibrosarcoma (RAF) protein targeting moiety; and
the L is a bond or a chemical linking moiety connecting the ULM and the PTM.
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Accused Products
Abstract
The present disclosure relates to bifunctional compounds, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A-RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.
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Citations
42 Claims
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1. A bifunctional compound having the chemical structure:
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ULM-L-PTM,or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof, wherein; the ULM is a small molecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase; the PTM is a small molecule comprising a rapidly accelerated fibrosarcoma (RAF) protein targeting moiety; and the L is a bond or a chemical linking moiety connecting the ULM and the PTM. - View Dependent Claims (2, 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, 40, 41, 42)
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4. The bifunctional compound according to claim 1, wherein the PTM is represented by chemical structure PTM-IIa or PTM-IIb:
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5. The bifunctional compound according to claim 4, wherein:
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when RPTM9 is the covalently joined position, RPTM7 and RPTM8 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM7 and RPTM8 are attached;
orwhen RPTM18 is the covalently joined position, RPTM9 and RPTM10 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM9 and RPTM10 are attached;
orwhen RPTM10 is the covalently joined position, RPTM8 and RPTM9 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM8 and RPTM9 are attached.
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6. The bifunctional compound according to claim 1, wherein the PTM is represented by chemical structure PTM-III:
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7. The compound according to claim 6, wherein:
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when RPTM12 is the covalently joined position, RPTM13 and RPTM14 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM13 and RPTM14 are attached, and/or RPTM15 and RPTM16 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM15 and RPTM16 are attached; when RPTM13 is the covalently joined position, RPTM12 and RPTM16 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM12 and RPTM16 are attached, and/or RPTM15 and RPTM16 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM15 and RPTM16 are attached;
orwhen RPTM16 is the covalently joined position, RPTM12 and RPTM13 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM12 and RPTM13 are attached, and/or RPTM13 and RPTM14 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM13 and RPTM14 are attached
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8. The bifunctional compound according to claim 1 or 2, wherein the PTM is represented by chemical structure PTM-IVa or PTM-IVb:
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9. The bifunctional compound according to claim 8, wherein:
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when RPTM24 is the covalently joined position, RPTM31 and RPTM32 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM31 and RPTM32 are attached, or RPTM29 and RPTM30 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM29 and RPTM30 are attached;
orwhen RPTM29 is the covalently joined position, RPTM24 and RPTM32 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM24 and RPTM32 are attached, and/or RPTM31 and RPTM32 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM31 and RPTM32 are attached;
or when RPTM32 is the covalently joined position, RPTM24 and RPTM29 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM24 and RPTM29 are attached, and/or RPTM29 and RPTM30 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM29 and RPTM30 are attached.
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10. The bifunctional compound according to claim 1, wherein the PTM is selected from the group consisting of PTM-1, PTM-2, PTM-3, PTM-4, PTM-5, PTM-6, PTM-7, and PTM-8:
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11. The bifunctional compound according to claim 1, wherein the ULM is selected from the group consisting of:
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12. The bifunctional compound according to claim 1, wherein ULM is a Von Hippel-Lindau (VHL) ligase-binding moiety (VLM) with a chemical structure represented by:
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13. The bifunctional compound according to claim 1, wherein ULM is a Von Hippel-Lindau (VHL) ligase-binding moiety (VLM) with a chemical structure represented by:
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14. The bifunctional compound according to claim 1, wherein the ULM has a chemical structure selected from the group of:
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15. The bifunctional compound according to claim 1, wherein the ULM comprises a group according to the chemical structure:
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16. The bifunctional compound according to claim 1, wherein the ULM comprises a group according to the chemical structure:
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17. The bifunctional compound according to claim 1, wherein the ULM is a cereblon E3 ligase-binding moiety (CLM) selected from the group coinsisting of a thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.
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18. The bifunctional compound according to claim 1, wherein the CLM has a chemical structure represented by:
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19. The bifunctional compound according to claim 1, wherein the CLM has a chemical structure represented by:
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20. The bifunctional compound according to claim 1, wherein the CLM has a chemical structure represented by:
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21. The bifunctional compound according to claim 1, wherein the ULM is a (MDM2) binding moiety (MLM) with a chemical moiety selected from the group consisting of a substituted imidazolines, a substituted spiro-indolinones, a substituted pyrrolidines, a substituted piperidinones, a substituted morpholinones, a substituted pyrrolopyrimidines, a substituted imidazolopyridines, a substituted thiazoloimidazoline, a substituted pyrrolopyrrolidinones, and a substituted isoquinolinones.
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22. The bifunctional compound according to claim 1, wherein the ULM is a IAP E3 ubiquitin ligase binding moiety (ILM) comprising the amino acids alanine (A), valine (V), proline (P), and isoleucine (I) or their unnatural mimetics.
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23. The bifunctional compound according to claim 1, wherein the ULM is a IAP E3 ubiquitin ligase binding moiety (ILM) comprising a AVPI tetrapeptide fragment or derivative thereof.
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24. The bifunctional compound according to claim 1, wherein the linker (L) comprises a chemical structural unit represented by the formula:
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-(AL)q-,wherein; (AL)q is a group which is connected to a ULM or PTM moiety; q is an integer greater than or equal to 1; each AL is independently selected from the group consisting of, a bond, CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NRL4, CO, CRL1═
CRL2, C≡
C, SiRL1RL2, P(O)RL1, P(O)ORL1, NRL3C(═
NCN)NRL4, NRL3C(═
NCN), NRL3C(═
CNO2)NRL4, C3-11cycloalkyl optionally substituted with 0-6 RL1 and/or RL2 groups, C3-11heteocyclyl optionally substituted with 0-6 RL1 and/or RL2 groups, aryl optionally substituted with 0-6 RL1 and/or RL2 groups, heteroaryl optionally substituted with 0-6 RL1 and/or RL2 groups, where RL1 or RL2, each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 RL5 groups; andRL1, RL2, RL3, RL4 and RL5 are, each independently, H, halo, C1-8alkyl, OC1-8alkyl, SC1-8alkyl, NHC1-8alkyl, N(C1-8alkyl)2, C3-11cycloalkyl, aryl, heteroaryl, C3-11heterocyclyl, OC1-8cycloalkyl, SC1-8cycloalkyl, NHC1-8cycloalkyl, N(C1-8cycloalkyl)2, N(C1-8cycloalkyl)(C1-8alkyl), OH, NH2, SH, SO2C1-8alkyl, P(O)(OC1-8alkyl)(C1-8alkyl), P(O)(OC1-8alkyl)2, CC—
C1-8alkyl, CCH, CH═
CH(C1-8alkyl), C(C1-8alkyl)═
CH(C1-8alkyl), C(C1-8alkyl)=C(C1-8alkyl)2, Si(OH)3, Si(C1-8alkyl)3, Si(OH)(C1-8alkyl)2, COC1-8alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-8alkyl, SO2N(C1-8alkyl)2, SONHC1-8alkyl, SON(C1-8alkyl)2, CONHC1-8alkyl, CON(C1-8alkyl)2, N(C1-8alkyl)CONH(C1-8alkyl), N(C1-8alkyl)CON(C1-8alkyl)2, NHCONH(C1-8alkyl), NHCON(C1-8alkyl)2, NHCONH2, N(C1-8alkyl)SO2NH(C1-8alkyl), N(C1-8alkyl) SO2N(C1-8alkyl)2, NH SO2NH(C1-8alkyl), NH SO2N(C1-8alkyl)2, NH SO2NH2.
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25. The bifunctional compound according to claim 24, wherein the linker (L) comprises a group represented by a general structure selected from the group consisting of:
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—
N(R)—
(CH2)m-O(CH2)n—
O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-OCH2-,—
O—
(CH2)m-O(CH2)n—
O(CH2)oO(CH2)p-O(CH2)q-O(CH2)r-OCH2-,—
O—
(CH2)m-O(CH2)n—
O(CH2)oO(CH2)p-O(CH2)q-O(CH2)r-O—
;—
N(R)—
(CH2)m-O(CH2)n—
O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O—
;—
(CH2)m-O(CH2)n—
O(CH2)oO(CH2)p-O(CH2)q-O(CH2)r-O—
;—
(CH2)m-O(CH2)n—
O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-OCH2-;
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26. The bifunctional compound according to claim 24, wherein the linker (L) is selected from the group consisting of:
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27. The bifunctional compound according to claim 24, wherein the linker (L) is selected from the group consisting of:
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28. The bifunctional compound according to claim 24, wherein the linker (L) is selected from the group consisting of:
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29. The bifunctional compound according to claim 1, wherein the linker (L) comprises the following chemical structure:
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30. The bifunctional compound according to claim 1, wherein the linker (L) comprises the following chemical structure:
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31. The bifunctional compounds according to claim 24, wherein the linker (L) is selected from the group consisting of:
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32. The bifunctional compound according to claim 24, wherein the linker (L) is a polyethylenoxy group optionally substituted with aryl or phenyl comprising from 1 to 10 ethylene glycol units.
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33. The bifunctional compound according to claim 24, wherein the linker is selected from the group consisting of:
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34. The bifunctional compound of claim 1, wherein the compound is selected from Table 1 through Table 42.
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35. The bifunctional compound according to claim 1, wherein the PTM is a small molecule comprising a B-RAF protein targeting moiety.
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36. A composition comprising an effective amount of a bifunctional compound according to claim 1, and a pharmaceutically acceptable carrier.
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37. The composition according to claim 30, wherein the composition further comprises at least one of an additional bioactive agent or another bifunctional compound of claim 1.
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38. The composition according to claim 37, wherein the additional bioactive agent is anti-cancer agent.
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39. A composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound according to claim 1 for treating a disease or disorder in a subject, the method comprising administering the composition to a subject in need thereof, wherein the compound is effective in treating or ameliorating at least one symptom of the disease or disorder.
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40. The composition according to claim 39, wherein the disease or disorder is associated with BRaf accumulation and aggregation.
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41. The composition according to claim 39, wherein the disease or disorder is cancer;
- cardiofaciocutaneous syndrome;
neurofibromatosis type 1;
Costello syndrome;
Noonan Syndrome;
or Lentigo, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retarded growth, Deafness (LEOPARD) syndrome associated with RAF accumulation and aggregation.
- cardiofaciocutaneous syndrome;
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42. The composition according to claim 41, wherein the cancer is renal cell carcinoma;
- pancreatic cancer, colorectal cancer;
lung cancer;
ovarian cancer;
thyroid cancer;
pilocytic astrocytoma;
prostate cancer;
gastric cancer;
hepatocellular carcinoma;
or melanoma.
- pancreatic cancer, colorectal cancer;
Specification