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CN-122029163-A - Chemical for targeting chromatin remodeling complexes and uses thereof

CN122029163ACN 122029163 ACN122029163 ACN 122029163ACN-122029163-A

Abstract

The present disclosure relates to compounds, compositions and methods for treating diseases or conditions mediated by aberrant bromodomain PHD-specific transcription factor (BPTF) activity.

Inventors

  • LIU QI
  • QI JUN
  • M.Y.Wang
  • K. HUBER
  • L. BAUER

Assignees

  • 丹娜-法伯癌症研究院
  • 牛津大学院长校长专家委员会

Dates

Publication Date
20260512
Application Date
20241001
Priority Date
20231002

Claims (20)

  1. 1. A compound having a structure represented by formula I or II: (I) Or (b) (II), Or a pharmaceutically acceptable salt or stereoisomer thereof, Wherein: Decreasing stator binding Cereblon (CRBN) or Hippel-Lindau (VHL) tumor suppressor, and The linker represents a moiety that covalently links the stator and the nitrogen atom.
  2. 2. The compound of claim 1, wherein the degradation determinant is represented by a structure selected from the group consisting of: (D1)、 (D2)、 (D3)、 (D4) And (D5), Wherein, the X is CH 2 or C (O); r 1 is absent, CH 2 , C≡C, NH, O, or a 5-to 11-membered monocyclic or bicyclic heterocyclic group containing 1 or 2 heteroatoms independently selected from N, O and S; x' is absent or C (O); y is N or CH, and R 2 is an optional substituent.
  3. 3. The compound of claim 2, wherein the down-solving stator is represented by formula D1.
  4. 4. A compound according to claim 3, wherein X is CH 2 .
  5. 5. A compound according to claim 3, wherein X is C (O).
  6. 6. The compound of claim 2, wherein the degradation determinant has formula D2.
  7. 7. The compound of claim 6, wherein X' is absent and R 2 is fluoro.
  8. 8. The compound of claim 2, wherein R 1 is absent or NH.
  9. 9. The compound of claim 2, wherein R 1 is a 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S.
  10. 10. The compound of claim 9, wherein R 1 is piperazinyl.
  11. 11. The compound of claim 2, wherein R 1 is a 9-membered bicyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S.
  12. 12. The compound of claim 11, wherein R 1 is 2, 7-diazaspiro [3.5] nonane.
  13. 13. The compound of claim 2, wherein the down-solving stator is represented by formula D4.
  14. 14. The compound of claim 13, wherein R 2 is methoxy.
  15. 15. The compound of claim 2, wherein the down-solving stator is represented by formula D5.
  16. 16. The compound of claim 1, wherein the degradation determinant is represented by D6: (D6) Or a stereoisomer thereof, or a mixture of two or more of the stereoisomers, Wherein: R 3 is hydrogen or optionally substituted C 1 -C 3 alkyl, or R 3 and R 4 together with the carbon atom to which they are attached form cyclopropyl; R 4 is hydrogen, methyl or ; R 5 is C (O) CR 6 R 7 R 8 , Or (b) ; R 6 and R 7 are hydrogen, or R 6 and R 7 together with the carbon atom to which they are attached form cyclopropyl; R 8 is hydrogen, fluoro, cyano or NMe 2 , and Y is hydrogen, 、 、 Or (b) ; Wherein the method comprises the steps of For the bond between the degradation determinant and the linker, provided that only one bond exists between the degradation determinant and the linker.
  17. 17. The compound of claim 16, wherein the down-solving stator is represented by any one of the following structures: (D6a)、 (D6b)、 (D6c)、 (D6d)、 (D6e)、 (D6f)、 (D6 g) or (D6 h), or a stereoisomer thereof, Wherein Y is O, NH or CH 2 .
  18. 18. The compound of claim 1, wherein the linker is an alkylene chain capable of being interrupted by and/or capped ：–O–、–S–、–N(R')–、–C≡C–、–C(O)–、–C(O)O–、–OC(O)–、–OC(O)O–、–C(NOR')–、–C(O)N(R')–、–C(O)N(R')C(O)–、–C(O)N(R')C(O)N(R')–、–N(R')C(O)–、–N(R')C(O)N(R')–、–N(R')C(O)O–、–OC(O)N(R')–、–C(NR')–、–N(R')C(NR')–、–C(NR')N(R')–、–N(R')C(NR')N(R')–、–OB(Me)O–、–S(O) 2 –、–OS(O)–、–S(O)O–、–S(O)–、–OS(O) 2 –、–S(O) 2 O–、–N(R')S(O) 2 –、–S(O) 2 N(R')–、–N(R')S(O)–、–S(O)N(R')–、–N(R')S(O) 2 N(R')–、–N(R')S(O)N(R')–、 at either or both ends with at least one of an optionally substituted C 3 -C 12 carbon-idenyl group, an optionally substituted 3-to 12-membered heterocyclylene group, an optionally substituted 5-to 12-membered heteroarylene group, or any combination thereof, wherein R' is H or C 1 -C 6 alkyl, wherein the interruption and one or both capping groups can be the same or different.
  19. 19. The compound of claim 18, wherein the linker is an alkylene chain having 3-11 alkylene units.
  20. 20. The compound of claim 18, wherein the linker is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。

Description

Chemical for targeting chromatin remodeling complexes and uses thereof RELATED APPLICATIONS The present application is based on the priority benefit of U.S. c. ≡119 (e) claiming U.S. provisional application No. 63/541,946 filed on 2 nd 10 th 2023, which is incorporated herein by reference in its entirety. Subsidized Projects facilitating the present application have funded from the Innovative drug initiative 2 Joint Utility (JU) according to the 35 < 875510 > gift agreement. JU was sponsored from the European Horizon 2020 institute and innovation program (europaan Union's horizons 2020 research and innovation programme), EFPIA and the swedish imperial college OF academy OF technology (KUNGLIGA TEKNISKA HOEGSKOLAN), diamond light source limited (DIAMOND LIGHT SOURCE LIMITED), the institute OF cancer in ontario (Ontario Institute for CANCER RESEARCH), the imperial higher education institution at the university OF mcgil (ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING MCGILL UNIVERSITY). Background Bromodomain PHD refers to a member of the family of mimic switches (ISWI) of transcription factors (BPTF), chromatin remodelling agents, mutated or overexpressed in a variety of cancer types. Chromatin modification plays a major role in tumorigenesis, chemotherapy resistance, and sensitivity to immune responses. To date, no chemical probes have been reported to selectively degrade BPTF. Reported small molecule inhibitors of BPTF have been shown to have off-target cytotoxic effects or to be ineffective in tumor cell antiproliferation. Thus, there is a need for compounds that provide effective inhibition of tumor cell proliferation while minimizing off-target cytotoxic effects in the treatment of cancer. Disclosure of Invention A first aspect of the present disclosure relates to a compound having a structure represented by formula I or II: (I) Or (b) (II), or a pharmaceutically acceptable salt or stereoisomer thereof, Wherein: Decreasing stator binding Cereblon (CRBN) or Hippel-Lindau (von Hippel Lindau) (VHL) tumor suppressor, and The linker represents a moiety that covalently links the stator and the nitrogen atom. Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula I or II, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. In another aspect of the present disclosure, a method of preparing a compound of formula (I) or (II) is provided. Another aspect of the present disclosure relates to a method of treating cancer involving aberrant BPTF activity, the method comprising administering to a subject in need thereof a compound of formula I or II, or a pharmaceutically acceptable salt or stereoisomer thereof. Drawings FIG. 1A is a heat map and FIG. 1B is a scatter plot showing dBPTF-2 selectivity to BPTF chemical proteomics using cell line K562. Figures 2A-2G are immunoblots showing the degradation of BPTF by a compound at a specified concentration. FIG. 2A shows NVS-BPTF-1, dBPTF-1, dBPTF-2 and dBPTF-3 using the cell line VAL after 24 hours. FIG. 2B shows dBPTF-2 using the cell line VAL after 8 hours. FIG. 2C shows dBPTF-2, dBPTF-4, dBPTF-5 and dBPTF-6 using the cell lines VAL after 24 hours. FIG. 2D shows dBPTF-2, dBPTF-6, dBPTF-7 and dBPTF-8 using the cell lines VAL after 24 hours. FIG. 2E shows dBPTF-2 and dBPTF-7 of the use of the cell line VAL after 6 hours. FIG. 2F shows dBPTF-2, dBPTF-9, dBPTF-10 and dBPTF-11 of the use of the cell lines VAL after 24 hours. FIG. 2G shows NVS-BPTF-1, dBPTF-2, dBPTF-12 and dBPTF-13 using the cell line VAL after 24 hours. Fig. 3A and 3B are immunoblots showing CRBN knockout rescue resolution. FIG. 3A shows BPTF degradation after 24 hours using cell lines 293T dBPTF-2, dBPTF-9 and dBPTF-11. FIG. 3B shows that dBPTF-2, dBPTF-9 and dBPTF-11 did not degrade BPTF when the cell line 293T CRBN KO was used after 24 hours. Fig. 4A and 4B are immunoblots showing BPTF degradation in different cancer types. FIG. 4A shows BPTF degradation after 24 hours using cell lines MCF7 (mammary gland) dBPTF-2, dBPTF-9 and dBPTF-11. FIG. 4B shows BPTF degradation after 24 hours using cell lines NCIH2030 (lung) dBPTF-2, dBPTF-9 and dBPTF-11. Fig. 5A (6 hours) and fig. 5B (20 hours) are graphs showing ternary complexes formation of 293T cells transfected with BPTF labeled with NanoLuc ® and CRBN labeled with HaloTag ® with various compounds. FIGS. 6A-6C show that NVS-BPTF-1B degrades BPTF in HiBiT cells using cell line 293T. FIG. 6A is a graph showing the detection of Nano-Glo ® HiBit cleavage after 6 hours. FIG. 6B is a graph showing the detection of Nano-Glo ® HiBit cleavage after 20 hours. Fig. 6C is a graph showing cell viability after 20 hours. FIGS. 7A and 7B show that NVS-BPTF-1B behaves consistently in assays. FIG. 7A is an immunoblot showing degradation of BPTF with NVS-BPTF-1B, TP-238-2 and TP-238-3 using cell line VAL after 8 hours. FIG. 7B is a graph showing the detection of Nano-