Jiankang Hu, Hongrui Xu, Tianbang Wu, Cheng Zhang, Hui Shen, Ruibo Dong, Qingqing Hu, Qiuping Xiang, Shuang Chai, Guolong Luo, Xiaoshan Chen, Yumin Huang, Xiaofan Zhao, Chao Peng, Xishan Wu, Bin Lin, Yan Zhang, Yong Xu
The transcriptional coactivator cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 have emerged as attractive therapeutic targets for human cancers such as acute myeloid leukemia (AML). Herein, we report the design, synthesis, and biological evaluation of a series of cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on the inhibitor CCS1477. The representative compounds 14g (XYD190) and 14h (XYD198) potently inhibited the growth of AML cells with low nanomolar IC50 values and effectively degraded CBP and p300 proteins in a concentration- and time-dependent manner...
April 22, 2024: Journal of Medicinal Chemistry