Application of Selective SMARCA2/4 PROTAC for Mutant Cancer Therapy

Important Compound Classes

Title

6-Substituted Pyridazine Compounds as SMARCA2 and/or SMARCA4 Degraders

Patent Publication Number

WO 2022/029617 A1 (URL: https://patents.google.com/patent/WO2022029617A1/en?oq=WO+2022%2f029617+A1)

Publication Date

February 10, 2022

Priority Application

IN202041033326

Priority Date

August 4, 2020

Inventors

Abbineni, C.; Samajdar, S.; Kuila, B.; Mukherjee, S.; Tatyasaheb Gore, S.

Assignee Company

Aurigene Discovery Technologies Limited [IN/IN]; 39-0, KIADB Industrial Area, Electronic City Phase II, Hosur Road, Bangalore 560100, India

Disease Area

Cancer

Biological Target

SMARCA2/4 Protein

Summary

Bromodomains (BRDs) are epigenetic protein–protein interaction modules that are involved in gene transcription. Most often, multiple bromodomains are present in nuclear complexes involved in chromatic remodeling, which complicates functional studies on the epigenetic reading process. In addition, bromodomain-containing proteins (BCPs) are often part of multivalent complexes, and many possess other chromatin recognition domains, such as plant homeodomain (PHD) fingers, PWWP domains (named after a conserved Pro-Trp-Trp-Pro motif), which are found in multiple copies of proteins that contain chromatin-association domains or in cell growth and differentiation transcription factors. The human genome encodes 61 BRDs in 46 BRD-containing proteins. Polybromo-1 protein (PB1, also referred to as BAF180 or PBRM1) is a component of the BRG1/BRM-associated factor (PBAF) complex, which is a human analog of the yeast switch/sucrose non-fermenting (SWI/SNF) complex. There are frequent mutations in various subunits of the mammalian SWI/SNF chromatin remodeling complex, and approximately 20% of human cancers are associated with somatic mutations in subunits of the SWI/SNF complex.

The SWI/SNF complexes contain either of the two closely related and evolutionarily conserved catalytic ATPase subunits, Brahma (BRM/SMARCA2) or Brahma-related gene 1 (BRG 1/SMARCA4), which share approximately 75% identify at the protein level. In human cancer, BRG1 seems to be one of the most frequently mutated subunit genes, whereas the BRM gene is rarely mutated. The BRG1/SMARCA4 mutations occur in 10–15% of lung adenocarcinomas, whereas BRM/SMARCA2 is essential for the growth of tumor cells that harbor loss of function mutations in BRGI/SMARCA4. Consequently, depletion of BRM in BRGl-deficient cancer cells leads to cell cycle arrest, induction of senescence, and increased levels of global H3K9me31. Furthermore, in some tumor types, mutations within the SWI/SNF complex lead to context-specific vulnerabilities, such as the requirement of SMARCA2 for survival of tumor cells lacking SMARCA4. Some studies have shown that SMARCA4 knockdown/modulation increases sensitivity to known chemotherapeutic agents, which may indicate that SMARCA4 targeting could also be an adjuvant therapy to existing chemotherapeutic approaches.

In light of the biological importance of SWI/SNF family complexes, chemical probes that target different bromodomains within the complex would constitute highly valuable tools to elucidate the exact function and therapeutic pertinence of each member, and approaches that lead to reduction or complete elimination of SMARCA2/4 may be needed. Small-molecule ligands targeting the bromodomains of SMARCA2 and SMARCA4 have been reported. Although cells lacking SMARCA4 activity are vulnerable to the loss of SMARCA2, SMARCA2/4 inhibitors have failed to phenocopy these anti-proliferative effects. SMARCA2/4BD inhibitors are thus precluded from use for the treatment of SMARCA4 mutant cancers but could provide attractive ligands for PROTAC (proteolysis-targeting chimeras) conjugation.

PROTACs are heterobifunctional molecules that contain as a ligand a target protein of interest connected via a linker to a ligand for an E3 ubiquitin ligase. Upon heterodimerization of the two bound proteins, the target protein is ubiquitinated and degraded by the proteasome in cells. Proteins that have been effectively degraded using these approaches include BRD4, RlPK2 and ERRS, BRD9, Erα and BCR/Abl, and Abl.

The disclosure in patent WO 2022/029617 A1 provides 6-substituted pyridazine compounds and pharmaceutical compositions that are useful as SMARCA2 and/or SMARCA4 degraders and as potential therapeutics for diseases or disorders dependent upon or mediated by SMARCA2/4.

Key Structures

Biological Assay

Western Blot and Cell Titer Glo assay.

Biological Data

The table below shows percentage of SMARCA2 or SMARCA4 degradation. Compounds 2, 5, 6, and 11 were screened and their EC₅₀ values (nM) determined, and all resulted in EC₅₀ values that were lower than 250 nM.^1,2,3,4,5,6

The author declares no competing financial interest.

Special Issue

Published as part of the ACS Medicinal Chemistry Letters virtual special issue “New Drug Modalities in Medicinal Chemistry, Pharmacology, and Translational Science”.