Kotagiri Sasikumar, Blazanin Nicholas, Xi Yuanxin, Han Yanyan, Qudratullah Md, Liang Xiaobing, Wang Yawen, Pandey Poonam, Mazhar Hira, Lam Truong Nguyen, Singh Anand Kamal, Wang Jing, Lissanu Yonathan
Department of Cardiovascular and Thoracic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Chem Biol. 2024 Dec 19;31(12):2069-2084.e9. doi: 10.1016/j.chembiol.2024.09.004. Epub 2024 Oct 7.
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.
基因组研究已经确定，在非小细胞肺癌（NSCLC）中，SWI/SNF（转换/蔗糖非发酵）染色质重塑复合物的亚基，包括SMARCA4和ARID1A，存在频繁突变。遗传学证据表明，旁系同源物SMARCA2与SMARCA4具有合成致死性，这表明SMARCA2是一个有价值的治疗靶点。然而，发现SMARCA2的选择性抑制剂一直具有挑战性。在此，我们利用构效关系（SAR）研究开发了YD23，一种靶向SMARCA2的强效且选择性的蛋白酶靶向嵌合体（PROTAC）。从机制上讲，我们表明SMARCA2的降解会诱导SMARCA4突变细胞中增强子景观的重编程，导致参与细胞增殖的基因增强子处的染色质可及性丧失。此外，我们确定YAP/TEAD是SMARCA2在驱动SMARCA4突变细胞生长中的关键伙伴。最后，我们表明YD23在SMARCA4突变的异种移植瘤中具有强大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。
