Anti-tumor efficacy of SMARCA degraders in pre-clinical models of cancer

SMARCA2/BRM and SMARCA4/BRG1 are the mutually exclusive DNA-dependent ATPases within the SWI/SNF complexes, which function in mobilizing nucleosomes to regulate transcription, DNA replication and repair, and higher-order chromosome dynamics. SMARCA4 is mutated in a number of cancers, which generally lack targetable oncogenes. Genetic silencing studies have established a requirement of SMARCA2 for survival of tumor cells lacking SMARCA4. SMARCA4-deficient patient population represents 10%-20% of NSCLC cases, ∼5% pancreatic cancer patients and ∼10% ovarian cancer patients where SMARCA2 is overexpressed. Interestingly, SMARCA4 is highly expressed without mutation in certain tumor types, where overexpression contributes to increased proliferation and survival. SMARCA4 knockdown in these tumors leads to inhibition of proliferation and also increase sensitivity to known chemotherapeutic agents, supporting the validity of targeting SMARCA4. Although genetic silencing of SMARCA2 leads to potent anti-proliferative activity in SMARCA4-deficient cancer cell lines, pharmacological studies with a probe capable of binding to SMARCA2 and SMARCA4 bromodomain have failed to show such an anti-proliferative phenotype. These findings triggered us to evaluate chemical degradation as an alternate approach to target SMARCA2/4 altered cancers. Optimization of bifunctional molecules with binding moieties for SMARCA2/4 and E3 ligase to induce proteasome-mediated degradation resulted in the identification of selective SMARCA2 and SMARCA4 degraders. These degraders showed selectivity against other bromodomain containing proteins such as BRD4, CBP and p300 in Western blot analysis. Functional analysis of a preferential SMARCA2 degrader in a panel of cell lines indicated a potent anti-proliferative activity in the context of SMARCA4 mutation. Additionally, these compounds displayed acceptable drug-like properties including solubility, metabolic stability and pharmacokinetics in mice. Dose-dependent tumor growth inhibition was observed in a SMARCA4-deficient lung cancer xenograft model and a syngeneic model of lymphoma at well-tolerated doses. Observed efficacy was correlated with the target degradation in the tumor supporting the potential to further develop them for cancer therapy. Based on the reported vulnerability of SMARCA4-deficient cell lines of diverse tumor origin to agents targeting PARP, PI3K/AKT and EZH2, combination effects with SMARC2 degrader are being interrogated. Citation Format: Leena Khare Satyam, Sanjita Sasmal, Manoj K. Pothuganti, Sreevidya M.R., Ashokk Ettam, Sireesha Nunna, Marla Roshaiah, Shankaraiah Chithaluru, Rangarao Pallepati, Amitkumar A. Pawar, Leela P. Narukulla, Raghunadh A. Sripathi, Suraj Tgore, Rakesh P. Nankar, Charamanna KB, Nagesh Gowda S, Kiran Aithal, Samiulla DS, Subhendu Mukherjee, Shekar Chelur, Kavitha Nellore, Girish Daginakatte, Murali Ramachandra, Susanta Samajdar. Anti-tumor efficacy of SMARCA degraders in pre-clinical models of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3844.