基因组研究已发现非小细胞肺癌 (NSCLC) 中 SWI/SNF（开关/蔗糖非发酵）染色质重塑复合物亚基（包括 SMARCA4 和 ARID1A）中的频繁突变。遗传证据表明旁系同源物 SMARCA2 对 SMARCA4 具有合成致死性，表明 SMARCA2 是一个有价值的治疗靶点。然而，SMARCA2 选择性抑制剂的发现一直具有挑战性。在这里，我们利用构效关系 (SAR) 研究开发了 YD23，这是一种针对 SMARCA2 的有效选择性蛋白水解靶向嵌合体 (PROTAC)。从机制上讲，我们表明 SMARCA2 降解会诱导 SMARCA4 突变细胞中增强子景观的重新编程，并导致参与细胞增殖的基因增强子的染色质可及性丧失。此外，我们确定了 YAP/TEAD 是 SMARCA2 驱动 SMARCA4 突变细胞生长的关键合作伙伴。最后，我们证明 YD23 在 SMARCA4 突变异种移植物中具有有效的肿瘤生长抑制活性。这些发现为开发 SMARCA2 降解剂作为针对 SMARCA4 突变肺癌的合成致死疗法提供了机制基础。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified YAP/TEADas key partners to SMARCA2 in driving growth of SMARCA4-mutant cells. Finally, we show that YD23 has potent tumor growth inhibitory activity in SMARCA4-mutant xenografts. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4-mutant lung cancers.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.