Abstract LB-258: Identification of SMARCA2/4 degraders for the treatment of SMARCA4-mutant and other cancers
Authors: Sasmal Sanjita , Satyam Leena K. , Pothuganti Manoj K. , Ettam Ashokk , Nunna Sireesha , Shareef Mohammed A. , Gopinath Sreevalsam , Mukherjee Subhendu , Ramachandra Murali , Samajdar Susanta 
Published: August 2018

The SWI/SNF complexes consist of one of two mutually exclusive DNA-dependent ATPases, BRG1/SMARCA4 or BRM/SMARCA2, together with core and accessory subunits that function in mobilizing nucleosomes to regulate transcription, DNA replication and repair, and higher-order chromosome dynamics. SMARCA2 (BRM) and SMARCA4 (BRG1), contain a bromodomain and an ATPase domain. The mammalian SWI/SNF complex functions as a tumor suppressor in many human malignancies. In addition to an essential role in pluripotency and development, genetic lesions of SWI/SNF complexes have been strongly linked to cancer development as components are mutated in many cancers. In some tumor types, mutations within the SWI/SNF complex lead to context specific vulnerabilities such as the requirement of SMARCA2 for survival of tumour cells lacking SMARCA4. This finding of SMARCA2/4 synthetic lethal relationship translates in vivo which emphasizes SMARCA2 as a promising therapeutic target for the treatment SMARCA4-mutant cancers. Moreover, the SMARCA4-deficient patient population generally lacks targetable oncogenes (such as mutant EGFR or ALK translocations), which further emphasizes the potential of developing SMARCA2 inhibitors. Previously, contrary to genetic silencing of SMARCA2 leading to potent anti-proliferative activity in SMARCA4-deficient cancer cell lines, pharmacological studies with a cell permeable probe capable of binding to SMARCA2 and SMARCA4 have failed to show such an anti-proliferative phenotype. These findings support that the ATPase domain, but not the bromodomain of SMARCA2, is the tractable therapeutic target for SMARCA4-deficient cancer. Significant hurdle in developing potent and selective ATPase inhibitors that must compete with intracellular concentrations of ATP (2-10 mM) triggered us to evaluate chemical degrader as an alternate approach. Herein we report the identification and characterization of potent SMARCA2/4 degraders. Design and SAR-based optimization of bifunctional molecules with binding moities for SMARCA2/4 and E3 ligase to induce proteosome-mediated degradation yielded compounds that potently degraded SMARCA2 alone or both SMARCA2 and SMARCA4. Selective binding to SMARCA2/4 was confirmed in biochemical assays followed by assessement of their cellular degradation potency in Western blot analysis. Selective degradation of SMARCA2/4 over other bromodomain containing protein such as BRD4 and CBP/p300 was also observed. Functional analysis of these compounds in a panel of cell lines indicated that the degradation of SMARCA2 or SMARCA2/4 resulted in potent anti-proliferative activity in selected cell lines that was not strictly dependent upon SMARCA4 status. Additionally, these compounds displayed reasonable drug-like properties including solubility, metabolic stability and pharmacokinetics in mice supporting their potential to fully evaluate the impact of SMARCA2/4 degradation and to develop them as a novel therapeutic approach.

Citation Format: Sanjita Sasmal, Leena K. Satyam, Manoj K. Pothuganti, Ashokk Ettam, Sireesha Nunna, Mohammed A. Shareef, Sreevalsam Gopinath, Subhendu Mukherjee, Murali Ramachandra, Susanta Samajdar. Identification of SMARCA2/4 degraders for the treatment of SMARCA4-mutant and other cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-258.