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EP-4734988-A1 - HETEROBIFUNCTIONAL COMPOUNDS AND METHODS OF USE THEREOF

EP4734988A1EP 4734988 A1EP4734988 A1EP 4734988A1EP-4734988-A1

Abstract

Disclosed herein are heterobifunctional compounds that include a BCL6-binding moiety and a moiety that binds to a bromodomain of a histone acetyltransferase (HAT), with the two moieties connected via a linker. Also disclosed herein are pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., to treat proliferative diseases such as cancers.

Inventors

  • CRABTREE, GERALD R.
  • SAROTT, Roman C.
  • NIX, Meredith N.
  • ZHANG, TINGHU
  • GRAY, NATHANAEL S.
  • GOURISANKAR, Sai
  • KROKHOTIN, Andrey

Assignees

  • The Board of Trustees of the Leland Stanford Junior University

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A compound of formula (I) A-L-B (I) or a pharmaceutically acceptable salt thereof, wherein: A is a BCL6-binding moiety; L is a linker; and B is a moiety that binds to the bromodomain of a histone acetyltransferase.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a moiety of formula:
  3. 4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is a moiety that binds to the bromodomain of p300 or CBP.
  4. 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein B is a moiety of formula:
  5. 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein B is a moiety of formula:
  6. 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (la):
  7. 8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein L is a direct bond or comprises any combination of -CHz-, -CH=CH-, -C=C~, -O-, -NR'-, -BR'-, -S-, -C(O)-, -C(NR')-, -S(O)-, -S(O)2-, arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties, wherein the arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties are independently unsubstituted or substituted with 1, 2, or 3 substituents.
  8. 9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein L is a direct bond or comprises any combination of -CH2-, -O-, -C(O)-, -NH-, -N(CH3)-, cycloalkylene, and heterocyclylene moieties.
  9. 10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein L comprises any combination of the following moieties: wherein p is 1, 2, 3, 4, 5, or 6; and q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein L has a formula selected from: wherein p is 1, 2, 3, 4, 5, or 6; and q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
  10. 11, 12, 13, 14, 15, or 16.
  11. 12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein L has a formula selected from:
  12. 13. The compound of claim 1, wherein the compound is selected from: and pharmaceutically acceptable salts thereof.
  13. 14. A pharmaceutical composition comprising a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  14. 15. A method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof.
  15. 16. The method of claim 14, wherein the proliferative disease is a cancer selected from a carcinoma, a sarcoma, and a hematologic malignancy.
  16. 17. The method of claim 15, wherein the cancer is a lymphoma.
  17. 18. The method of claim 16, wherein the cancer is a diffuse large B-cell lymphoma.
  18. 19. A compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  19. 20. A compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, for use in treating a proliferative disease.
  20. 21. The compound of claim 20, wherein the proliferative disease is a cancer selected from a carcinoma, a sarcoma, and a hematologic malignancy.

Description

HETEROBIFUNCTIONAL COMPOUNDS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63/511,374, filed on June 30, 2023, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with Government support under contracts CA163915, CA276167, and MH126720 awarded by the National Institutes of Health. The Government has certain rights in the invention. SEQUENCE LISTING STATEMENT The contents of the electronic sequence listing titled STDU2_42137_601_SequenceListing.xml (Size: 2,854 bytes; and Date of Creation: June 28, 2024) is incorporated herein by reference in its entirety. TECHNICAL FIELD Disclosed herein are heterobifunctional compounds that include a BCL6-binding moiety and a moiety that binds to a bromodomain of a histone acetyltransferase (HAT), with the two moi eties connected via a linker. Also disclosed herein are pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., to treat proliferative diseases such as cancers. BACKGROUND One of the major accomplishments of cancer biology within the last 40 years has been the identification of cancer drivers that, when mutated or otherwise misregulated, drive the proliferation, spread, or survival of cancer cells (Weinberg, Science 230(4727), 770-776 (1985); Davoli el al. Cell 155, 948-962 (2013); Sanchez- Vega el al. Cell 173, 321-337 e310 (2018); Denny el al. Cell 166, 328-342 (2016)). The cancer drivers have been largely recognized from human genetic studies of specific tumors, and can be grouped into tumor suppressors that prevent cancer from developing, or oncogenes that contribute directly to the proliferation or spread of the cancer at the expense of the organism. During the past forty years, parallel studies conducted largely in the laboratories of developmental biologists have identified pathways of programed cell death that kill specific populations of cells that have made mistakes in developmental programs or have errors in DNA replication or repair (Hengartner et al. Cell 76, 665-676 (1994); Strasser et al. Annu. Rev. Biochem. 69, 217-245 (2000)). These pathways of cell death have been evolutionarily perfected for over 100 million years and are remarkably effective. Indeed, about 60 billion of our cells are killed every day by these mechanisms (Alberts et al. in Molecular Biology of the Cell (2002)). The genes, proteins, and biochemical pathways inducing (pro-apoptotic) and preventing (anti- apoptotic) programmed cell death are well-known and reasonably well -understood. SUMMARY Disclosed herein is a compound of formula (I) A-L-B (I) or a pharmaceutically acceptable salt thereof, wherein: A is a BCL6-binding moiety; L is a linker; and B is a moiety that binds to the bromodomain of a histone acetyltransferase. In some embodiments, A is a moiety of formula: In some embodiments, A is a moiety of formula: In some embodiments, B is a moiety that binds to the bromodomain of p300 or CBP. In some embodiments, B is a moiety of formula: In some embodiments, B is a moiety of formula: In some embodiments, the compound is a compound of formula (la): In some embodiments, L is a direct bond or comprises any combination of -CH2-, - CH=CH-, -C=C-, -O-, -NR'-, -BR'-, -S-, -C(O)-, -C(NR')-, -S(O)-, -S(O)2-, aiylene, heteroarylene, cycloalkylene, and heterocyclylene moieties, wherein the arylene, heteroarylene, cycloalkylene, and heterocyclylene moieties are independently unsubstituted or substituted with 1, 2, or 3 substituents. In some embodiments, L is a direct bond or comprises any combination of -CH2-, -O-, -C(O)-, -NH-, -N(CH3)-, cycloalkylene, and heterocyclylene moieties. In some embodiments, L comprises any combination of the following moieties: wherein p is 1, 2, 3, 4, 5, or 6; and q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In some embodiments, L has a formula selected from: wherein p is 1, 2, 3, 4, 5, or 6; and q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In some embodiments, L has a formula selected from: In some embodiments, the compound is selected from: and pharmaceutically acceptable salts thereof. Also disclosed herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Also disclosed herein is a method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the proliferative disease is a cancer selected from a carcinoma, a sarcoma, and a hematologic malignancy. In some embodiments, the cancer is a lymphoma. In some embodiments, a diffuse large B-cell lymphoma. Also disclosed herein is a compound of form