Yang Tianqiong, Wei Wei, Zhang Qi, Chen Xin, Xu Kaiyan, Su Xingping, Yue Lin, Gao Jiuyu, Wang Ningyu, Cao Yu, Yu Luoting, Liu Zhihao
Department of Emergency Medicine and Laboratory of Emergency Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China.
Eur J Med Chem. 2025 Jun 5;290:117521. doi: 10.1016/j.ejmech.2025.117521. Epub 2025 Mar 19.
SMARCA2/4, a pair of mutually exclusive core catalytic subunits of the chromatin remodeling complex SWI/SNF, play essential roles in regulating gene transcription. Given the pivotal role of SMARCA2/4 in sustaining the oncogenic transcription program and promoting proliferation in acute myeloid leukemia (AML), the development of non-selective degraders holds practical therapeutic implications. Herein, we designed and synthesized a series of proteolysis-targeting chimeras (PROTACs) by conjugating the VHL ligand to a SMARCA2/4 bromodomain ligand, 2-(6-amino-5-phenylpyridazin-3-yl)phenol, using various linkers. Preliminary evaluations identified A11 as the most potent molecule that efficiently degraded SMRACA2 (DC = 3.0 nM, D = 98 %) and SMARCA4 (DC = 4.0 nM, D = 98 %). A11 significantly inhibited the proliferation of hematological cancer cell lines, including MV-4-11, MOLM-13 and SU-DHL-4. It decreased the levels of SMARCA2/4 through the ubiquitin-proteasome system. Global proteome analysis revealed that A11 was able to selectively target and degrade SMARCA2/4. Additionally, A11 caused cell cycle arrest at the G0/G1 phase and induced cell apoptosis in MV-4-11 and MOLM-13 cells. It also blocked the oncogenic activity of MYC and other disease-related genes in AML cells. Overall, our data clarified that A11 is a promising SMARCA2/4 degrader for cancer therapy, which is worthy of further evaluation.
SMARCA2/4是染色质重塑复合物SWI/SNF中一对相互排斥的核心催化亚基，在调节基因转录中起重要作用。鉴于SMARCA2/4在维持急性髓系白血病（AML）的致癌转录程序和促进增殖方面的关键作用，开发非选择性降解剂具有实际的治疗意义。在此，我们通过将VHL配体与SMARCA2/4溴结构域配体2-(6-氨基-5-苯基哒嗪-3-基)苯酚结合，并使用各种连接子，设计并合成了一系列靶向蛋白降解嵌合体（PROTAC）。初步评估确定A11是最有效的分子，它能有效降解SMRACA2（DC = 3.0 nM，D = 98%）和SMARCA4（DC = 4.0 nM，D = 98%）。A11显著抑制血液系统癌细胞系的增殖，包括MV-4-11、MOLM-13和SU-DHL-4。它通过泛素-蛋白酶体系统降低SMARCA2/4的水平。全蛋白质组分析表明，A11能够选择性地靶向并降解SMARCA2/4。此外，A11导致MV-4-11和MOLM-13细胞在G0/G1期发生细胞周期阻滞并诱导细胞凋亡。它还阻断了AML细胞中MYC和其他疾病相关基因的致癌活性。总体而言，我们的数据表明A11是一种有前景的用于癌症治疗的SMARCA2/4降解剂，值得进一步评估。
