2. Academic Validation
  3. Discovery of a Promising CBP/p300 Degrader XYD129 for the Treatment of Acute Myeloid Leukemia

Discovery of a Promising CBP/p300 Degrader XYD129 for the Treatment of Acute Myeloid Leukemia

  • J Med Chem. 2024 Jun 13;67(11):9194-9213. doi: 10.1021/acs.jmedchem.4c00335.
Tianbang Wu 1 2,  Jiankang Hu 2 3,  Xiaofan Zhao 4,  Cheng Zhang 2,  Ruibo Dong 2 5,  Qingqing Hu 2,  Hongrui Xu 4,  Hui Shen 2,  Xiaohan Zhang 6,  Yan Zhang 2,  Bin Lin 1,  Xishan Wu 2,  Qiuping Xiang 7,  Yong Xu 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 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.
  • 3 University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing, 100049, China.
  • 4 Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 511436, China.
  • 5 School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, China.
  • 6 Analysis and Testing Center, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 7 Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang 315010, China.
PMID: 38829718 DOI: 10.1021/acs.jmedchem.4c00335
Abstract

The epigenetic target CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) and its homologue p300 were promising therapeutic targets for the treatment of acute myeloid leukemia (AML). Herein, we report the design, synthesis, and evaluation of a class of CBP/p300 PROTAC degraders based on our previously reported highly potent and selective CBP/p300 inhibitor 5. Among the compounds synthesized, 11c (XYD129) demonstrated high potency and formed a ternary complex between CBP/p300 and CRBN (AlphaScreen). The compound effectively degraded CBP/p300 proteins and exhibited greater inhibition of growth in acute leukemia cell lines compared to its parent compound 5. Furthermore, 11c demonstrated significant inhibition of tumor growth in a MOLM-16 xenograft model (TGI = 60%) at tolerated dose schedules. Our findings suggest that 11c is a promising lead compound for the treatment of AML.

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