Discovery of\nPotent,\nHighly Selective, and Efficacious\nSMARCA2 Degraders

We\ndescribe the identification of selective SMARCA2, VHL-based\nheterobifunctional degraders. Structurally novel indolo[1,2-<i>a</i>]quinazolin-5(7<i>H</i>)-one SMARCA bromodomain\nbinders were optimized and then converted to SMARCA2 degraders by\nlinking them to well-defined VHL ligands. Our exploration led to the\ndiscovery of potent and selective degraders of SMARCA2 over the SMARCA4\nparalog, leading to potent and selective growth inhibition of SMARCA4\nmutant versus wild type cell lines. We further highlight the optimization\nof the pharmacokinetic profile of a subset of compounds leading to\npotent and selective degradation of SMARCA2 in the xenograft model.\nThese compounds provide valuable tools with desirable properties for\ncontinued exploration of the biology defining the susceptibility of\nSMARCA4 mutant cancers to selective loss of SMARCA2.