Abstract 1144: Orally bioavailable SMARCA2 degraders with exceptional selectivity and potency
Authors: Abbineni Chandrasekhar , Satyam Leena Khare , Kuila Bilash , Ettam Ashok , Rawoof Khaji Abdul , MR Sreevidya , Dukare Sandeep Vitthal , Gore Suraj T. , Nankar Rakesh P. , Ahuja Vijay Kamal , KB Charamanna , Goyal Megha , Aithal Kiran , DS Samiulla , Mukherjee Subhendu , Antony Thomas , Giri Sanjeev , Chelur Shekar , Nellore Kavitha , Daginakatte Girish , Ramachandra Murali , Samajdar Susanta 
Published: July 2021

Background: SMARCA2 (BRM) and SMARCA4 (BRG1) are two mutually exclusive DNA-dependent ATPases of the SWI/SNF complex, which function in mobilizing nucleosomes to regulate transcription, DNA replication/repair and chromosome dynamics. SMARCA4 is known to be mutated in number of cancers lacking targetable oncogenes, with SMARCA4-mutant patient population representing 10%-20% of NSCLC, 100% small cell ovarian cancer (hypercalcemic type), 28% skin cancer, 16% glioma and 14% colon cancer. Genetic studies have established the necessity of SMARCA2 for survival of tumor cells lacking 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 bromodomains have failed to recapitulate such anti-proliferative effects. This prompted us to evaluate targeted protein degradation as an alternate approach to target SMARCA4 altered cancers.

Methods and Results: A variety of hetero bi-functional molecules were synthesized by conjugating selective SMARCA2/4 bromodomain inhibitors with either VHL or CRBN E3-ligase specific ligands. Rational design approach guided by our proprietary ternary complex modeling algorithm, ALMOND (ALgorithm for MOdeling Neosubstrate Degraders) resulted in the identification of highly selective SMARCA2 degraders. The lead compound, AU-19820 showed &gt; 10000-fold selectivity for SMARCA2 degradation versus other homologous proteins in tested cell lines. AU-19820 demonstrated potent anti-proliferative activity in SMARCA4 mutant but not in SMARCA2/4 proficient cell lines. This compound displayed favorable IV PK profile in rodents along with clean CYP profile. Additionally, the lead compound exhibited significant tumor growth inhibition in RERF-LC-A1 (SMARCA4 mutant lung cancer) xenograft model when dosed via i.v. route. Efficacious exposures were well tolerated with excellent tumor penetration. The compound also demonstrated moderate oral bioavailability in mouse. Efforts are in progress to improve this further by SAR modifications and exploiting prodrug approach.

Conclusions: Potent and extremely selective SMARCA2 protein degraders were identified by conjugating SMARCA2/4 inhibitors with known VHL or CRBN ligands. SMARCA2 vs SMARCA4 selectivity handles have been very well explored with expandable SAR. Lead compound also displayed a synthetic lethality phenotype in SMARCA4 mutant cancer models while sparing SMARCA2/4 proficient ones. Further optimization of the oral bioavailability and evaluation of efficacy through oral route as well as intermittent IV dosing are planned.

Citation Format: Chandrasekhar Abbineni, Leena Khare Satyam, Bilash Kuila, Ashok Ettam, Khaji Abdul Rawoof, Sreevidya MR, Sandeep Vitthal Dukare, Suraj T. Gore, Rakesh P. Nankar, Vijay Kamal Ahuja, Charamanna KB, Megha Goyal, Kiran Aithal, Samiulla DS, Subhendu Mukherjee, Thomas Antony, Sanjeev Giri, Shekar Chelur, Kavitha Nellore, Girish Daginakatte, Murali Ramachandra, Susanta Samajdar. Orally bioavailable SMARCA2 degraders with exceptional selectivity and potency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1144.