2. Academic Validation
  3. Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity

Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity

  • J Med Chem. 2024 May 9;67(9):6952-6986. doi: 10.1021/acs.jmedchem.3c02195.
Jiankang Hu 1 2,  Hongrui Xu 3 4,  Tianbang Wu 1 5,  Cheng Zhang 1,  Hui Shen 1,  Ruibo Dong 1 6,  Qingqing Hu 1,  Qiuping Xiang 7 8,  Shuang Chai 1,  Guolong Luo 1,  Xiaoshan Chen 1 2,  Yumin Huang 1 2,  Xiaofan Zhao 3 4,  Chao Peng 9,  Xishan Wu 1,  Bin Lin 5,  Yan Zhang 1,  Yong Xu 1 5
Affiliations

Affiliations

  • 1 China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 2 University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
  • 3 Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 4 Guangzhou Medical University, Guangzhou 511436, China.
  • 5 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 6 School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, China.
  • 7 Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, China.
  • 8 Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang 315010, China.
  • 9 Jiangsu S&T Exchange Center with Foreign Countries, No. 175 Longpan Road, Nanjing 210042, China.
PMID: 38649304 DOI: 10.1021/acs.jmedchem.3c02195
Abstract

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. Mechanistic studies confirmed that 14g and 14h can selectively bind to CBP/p300 bromodomains and induce CBP and p300 degradation in bromodomain family proteins in a CRBN- and proteasome-dependent manner. 14g and 14h displayed remarkable antitumor efficacy in the MV4;11 xenograft model (TGI = 88% and 93%, respectively). Our findings demonstrated that 14g and 14h are useful lead compounds and deserve further optimization and activity evaluation for the treatment of human cancers.

Figures
Products