SMD-3236

Description

SMD-3236 is a SMARCA2-targeted PRAOTAC degrader designed based on SMARCA ligands and VHL-1 ligands, with long-lasting antitumor activity in vivo. SMARCA2 is a synthetic lethal target in SMARCA4-deficient cancer cells, and SMD-3236 has a 2000-fold selectivity for degradation of SMARCA2 over SMARCA4, with a DC50 1 nM and a Dmax 95 %. SMD-3236 can induce SMARCA2 loss in tumor tissues while retaining SMARCA4 protein, and inhibit tumor growth in the H838 smarca4-deficient human cancer xenograft model. SMD-3236 is composed of target protein ligand red part SMI-1074 HY-170817 , PROTAC linker black part trans-4-Ethynylcyclohexyl methyl methanesulfonate HY-170825 , and E3 ligase ligand blue part SMARCA2 ligand-14 HY-170826 , of which the E3 ligase ligand and linker form a conjugate E3 Ligase Ligand-linker Conjugate 159 HY-170827 .