The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
J Med Chem. 2022 Aug 25;65(16):11034-11057. doi: 10.1021/acs.jmedchem.2c00257. Epub 2022 Aug 4.
Aberrant hyperactivation of cyclins results in carcinogenesis and therapy resistance in cancers. Direct degradation of the specific cyclin or cyclin-dependent kinase (CDK)-cyclin complex by small-molecule degraders remains a great challenge. Here, we applied the first application of hydrophobic tagging to induce degradation of CDK9-cyclin T1 heterodimer, which is required to keep productive transcription of oncogenes in cancers. was identified as a potent small-molecule degrader of CDK9-cyclin T1. Quantitative and time-resolved proteome profiling exhibited induced selective and synchronous degradation of CDK9 and cyclin T1. The expressions of androgen receptor (AR) and cMyc were reduced by in 22RV1 cells. exhibited enhanced anti-proliferative and pro-apoptotic effects compared with its parental CDK9 inhibitor and suppressed downstream signaling of CDK9 and AR more effectively than . Moreover, inhibited AR and Myc-driven oncogenic transcriptional programs and exerted stronger inhibitory effects on several intrinsic target genes of AR than the monomeric CDK9 PROTAC ().
细胞周期蛋白的异常激活导致癌症的发生和治疗耐药性。通过小分子降解剂直接降解特定的细胞周期蛋白或细胞周期蛋白依赖性激酶（CDK）-细胞周期蛋白复合物仍然是一个巨大的挑战。在这里，我们首次应用疏水标记诱导 CDK9-细胞周期蛋白 T1 异二聚体的降解，这是癌症中保持致癌基因有效转录所必需的。被鉴定为一种有效的 CDK9-细胞周期蛋白 T1 小分子降解剂。定量和时间分辨的蛋白质组谱分析显示，诱导 CDK9 和细胞周期蛋白 T1 的选择性和同步降解。在 22RV1 细胞中，雄激素受体（AR）和 cMyc 的表达被 降低。与亲本 CDK9 抑制剂 相比， 表现出更强的抗增殖和促凋亡作用，并且比 更有效地抑制 CDK9 和 AR 的下游信号转导。此外， 抑制 AR 和 Myc 驱动的致癌转录程序，并对 AR 的几个固有靶基因产生比单体 CDK9 PROTAC ()更强的抑制作用。
