Preclinical Characterization of SMARCA2-Selective Monovalent Direct Degraders

Presentation

ENA

October 22, 2024

SMARCA2 and SMARCA4 are essential, yet redundant, catalytic subunits of human BAF complexes, which are involved in controlling gene expression through the remodeling of chromatin structure. In a subset of solid tumors, SMARCA4 is commonly mutated, rendering SMARCA4-deficient cancer cells dependent on SMARCA2 for viability. This synthetic lethal relationship may provide effective and safe treatment options for patients with SMARCA4-deficient tumors through the development of SMARCA2-selective degraders. To enable degrader discovery, we utilized a monovalent direct degrader strategy where small molecules are designed to bind the target protein and induce its degradation through the recruitment of an E3 ligase complex. The work detailed here highlights the characterization of our selective and orally bioavailable monovalent direct degraders of SMARCA2.