Search

US-12617787-B2 - Merged scaffold TAF1 inhibitors

US12617787B2US 12617787 B2US12617787 B2US 12617787B2US-12617787-B2

Abstract

Disclosed are inhibitors for TAF1. Methods of using the disclosed compounds to treat cancer are also disclosed.

Inventors

  • Justin M. Lopchuk
  • Ernst Schonbrunn
  • Zachary SHULTZ
  • Md Rezaul KARIM
  • Jiandong Chen

Assignees

  • H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC.

Dates

Publication Date
20260505
Application Date
20211130

Claims (20)

  1. 1 . A compound of Formula II or a pharmaceutically acceptable salt thereof, wherein: R 30 is selected from R 30a or —NH—R 30a ; R 30a is selected from unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, substituted or unsubstituted cycloalkyl, and unsubstituted or substituted heterocycloalkyl; R 31a and R 31b are brought together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl ring or a substituted or unsubstituted heterocycloalkyl ring; R 32 is selected from R 32a or —NH—R 32b ; R 32a is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, —(C 1 -C 6 alkyl)-(substituted or unsubstituted aryl), —(C 1 -C 6 alkyl)-(substituted or unsubstituted heteroaryl), —(C 1 -C 6 alkyl)-(substituted or unsubstituted cycloalkyl), and —(C 1 -C 6 alkyl)-(substituted or unsubstituted heterocyloalkyl); and R 32b is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, —(C 1 -C 6 alkyl)-(substituted or unsubstituted aryl), —(C 1 -C 6 alkyl)-(substituted or unsubstituted heteroaryl), —(C 1 -C 6 alkyl)-(substituted or unsubstituted cycloalkyl), and —(C 1 -C 6 alkyl)-(substituted or unsubstituted heterocyloalkyl).
  2. 2 . The compound of claim 1 , wherein R 30 is R 30a .
  3. 3 . The compound of claim 1 , wherein R 30 is —NH—R 30a .
  4. 4 . The compound of claim 1 , wherein R 30a is unsubstituted or substituted aryl.
  5. 5 . The compound of claim 1 , wherein R 30a is unsubstituted or substituted heteroaryl.
  6. 6 . The compound of claim 1 , wherein R 30a unsubstituted or substituted heterocycloalkyl.
  7. 7 . The compound of claim 1 , wherein R 30 is selected from:
  8. 8 . The compound of claim 1 , wherein R 31a and R 31b are brought together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl ring.
  9. 9 . The compound of claim 1 , wherein R 31a and R 31b are brought together with the carbon to which they are attached to form a substituted or unsubstituted heterocycloalkyl ring.
  10. 10 . The compound of claim 1 , wherein R 31a and R 31b are brought together with the carbon to which they are attached to form:
  11. 11 . The compound of claim 1 , wherein R 32 is R 32a .
  12. 12 . The compound of claim 11 , wherein R 32a is C 1 -C 6 alkyl or —(C 1 -C 6 alkyl)-(substituted or unsubstituted aryl).
  13. 13 . The compound of claim 11 , wherein R 32a is methyl.
  14. 14 . The compound of claim 1 , wherein R 32 is —NH—R 32b .
  15. 15 . The compound of claim 14 , wherein R 32b is hydrogen or —(C 1 -C 6 alkyl)-(substituted or unsubstituted aryl).
  16. 16 . The compound of claim 1 , wherein R 32 is selected from:
  17. 17 . The compound of claim 1 , wherein the compound is selected from:
  18. 18 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  19. 19 . A method for the treatment of a disorder of uncontrolled cellular proliferation associated with TAF1 dysfunction in a mammal comprising the step of administering to the mammal an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
  20. 20 . The method of claim 19 , wherein the disorder is cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a United States National Phase Patent Application of International Patent Application No. PCT/US2021/061121, filed Nov. 30, 2021, which claims the benefit of priority to U.S. Provisional Application No. 63/119,287, filed Nov. 30, 2020, the disclosure of which is incorporated herein by reference in its entirety. BACKGROUND Bromodomains (BRD) are highly conserved epigenetic “reader” modules that specifically recognize N-acetylated lysine (KAc) residues on histones and other proteins. Bromodomain-containing proteins control numerous functions including gene transcription and chromatin remodeling, gene splicing, protein scaffolding and signal transduction, and therefore, play fundamental roles in cell proliferation and division. A number of BRD-containing proteins, particularly those of the bromodomain and extra-terminal (BET) family, have been linked to tumorigenesis and inflammatory diseases. The landmark discoveries of potent small molecule inhibitors of BET bromodomains provided chemical tools to explore the function of proteins such as BRD4 in disease states for the first time. Since then several BRD4 inhibitors have entered clinical trials for oncology and cardiovascular indications. More recently, inhibitors targeting non-BET bromodomains, for which the physiological functions are not yet well understood, have been the subject of intense efforts in academia and pharmaceutical industry alike. Such inhibitors are valuable probes to unravel the function of bromodomains outside the BET family, their relevance in cancer and their potential as drug targets. The bromodomain-containing protein TAF1 (TATA-box binding protein associated factor 1) is a subunit of the core promoter recognizing complex TFIID involved in general transcription. It is composed of several domains, a TBP (TATA binding protein) binding domain, an N-terminal kinase domain, a domain of unidentified function (DUF3591), a histone acetyltransferase domain, a winged-helix domain, a zinc knuckle motif, a tandem bromodomain (BD1 and BD2), a serine rich acidic tail domain, and a C-terminal kinase domain (FIG. 1). Recently, genomic landscape studies identified TAF1 as a significantly mutated gene in uterine serous carcinoma, and TAF1 overexpression has been described as a major factor for the high mitotic activity of human lung and breast carcinoma cells. TAF1 has been reported to inactivate p53 through phosphorylation at Thr55, translocating p53 to the cytoplasm and Mdm2-mediated degradation to induce G1/S-transition.24-26 Upon DNA damage, diacetylated p53 (K373ac and K382ac) directly interacts with the bromodomains of TAF1 to initiate gene transcription. Inactivation of TAF1 has been associated with activation of DNA damage response, similar to that mediated by ATR (Ataxia telangiectasia and Rad3-related protein). Temperature-sensitive mutations in the putative HAT domain of TAF1 caused p53 activation and cell cycle arrest, hallmarks of an ATR-mediated DNA damage response. Although deregulation of gene transcription and evolving plasticity are the underlying cause of ever increasing drug resistance in cancer, TAF1 remains an underexplored target for the development of drugs aimed at uncontrolled gene transcription. Recent advancements in chemical biology and drug development indicate that targeting the basal transcription machinery is a viable means to develop promising new drugs. However, none of these approaches addressed the targeted inhibition of TAF1. To date, only few bromodomain inhibitors of TAF1 have been reported, with compounds BAY299 and GNE-371 being the most potent. Activity of these two compounds against the cancer cell lines tested was weak or not reported, but antiproliferative synergy with the BET inhibitor JQ1 was demonstrated. No TAF1 inhibitor has reached the clinic, and biological effects of inhibiting the bromodomain of TAF1 have not been reported yet. Combined, the present knowledge suggests that TAF1 is a promising yet underexplored target for the development of small molecule inhibitors directed at the transcription machinery of cancer cells through an epigenetic mechanism of action. There is a need for compositions and methods for chemical inhibition of the bromodomain of TAF1 alone and in combination with ATR in cancer. The precise role of the tandem bromodomain of TAF1 in the upregulation of oncogenic or inactivation of apoptotic pathways is unclear, and the effect of chemical TAF1 inhibition on transcriptional activity has not been reported yet. Previously, it was shown that TAF1 regulates cyclin A and D1 gene expression, Rb phosphorylation, DNA damage response (DDR) pathways and p21/p27 expression. However, the contribution of bromodomains in these signaling pathways is not known. Inhibiting the DDR has become a therapeutic concept in cancer therapy. Resistance to genotoxic therapies has been associated with increased DDR signaling, and many cancers are depe