Abstract 4606: Rational development of novel DCAF16-mediated SMARCA2 selective Targeted Glues™ for the treatment of SMARCA4 deficient tumors

Abstract SMARCA2 and SMARCA4 are mutually exclusive catalytic subunits of the SWI/SNF chromatin remodelling complex. In non-small cell lung cancer (NSCLC), SMARCA4 mutations are observed in >5% patients and are associated with poor prognosis and advanced disease. Selective degradation of SMARCA2 exploits paralogue dependency in SMARCA4-deficient tumors to impact disease burden with minimal toxicity in normal tissues. Here, we report the rational design and optimisation of a novel class of SMARCA2 degraders that exploit a Targeted Glue™ mechanism to induce DCAF16-dependent proteasomal degradation. Amphista’s degraders potently drive >95% SMARCA2 degradation within 4 hours, resulting in deep suppression of biomarkers KRT80 and PLAU in vitro. Further, we observe exceptional degradation specificity for SMARCA2, as revealed by global proteomics and, critical for a best-in-class molecule, achieve near complete selectivity over SMARCA4 in a SMARCA4 WT model. Comprehensive mode of action studies, including E3-ligase knock-out and cysteine mutant rescue experiments demonstrate that our SMARCA2 Targeted Glues™ induce degradation via selective recruitment of DCAF16 and covalent interaction with a single DCAF16 cysteine residue. Structural studies, including generation of multiple high resolution (sub-3Å) cryo EM ternary complex structures have enabled informed structure-activity relationship optimisations of degradation potency, kinetics and selectivity. Consequently, optimised compounds can deliver fast, deep degradation of SMARCA2 as demonstrated in-vivo in a disease-relevant SMARCA4 mutant model. We have achieved compound profiles that uniquely position Amphista to deliver class-leading SMARCA2 degraders for the treatment of SMARCA4-mutant NSCLC. Citation Format: James T. Lynch,Martin Ambler,Nicole Zordan,Claudia De Fusco,Laura Casares Perez,Kathryn Bosson,Alexander Fawcett,Paula MacGregor,Tarun Narwani,Colin T. Davies,Mahad Gatti Lou,Edward Hooper-Greenhill,Liliana Greger,Giles A. Brown,Martin Pass,Louise K. Modis. Rational development of novel DCAF16-mediated SMARCA2 selective Targeted Glues™ for the treatment of SMARCA4 deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4606.