2. Academic Validation
  3. Discovery of p300 histone acetyltransferase inhibitors bearing an imidazo[4,5-b]pyridine-2-one scaffold for the treatment of multiple myeloma

Discovery of p300 histone acetyltransferase inhibitors bearing an imidazo[4,5-b]pyridine-2-one scaffold for the treatment of multiple myeloma

  • Eur J Med Chem. 2026 Apr 5:307:118646. doi: 10.1016/j.ejmech.2026.118646.
Ying Xiong 1,  Xiaoxue Tan 2,  Hong Yang 3,  Yujie Wang 1,  Qiongyu Shi 3,  Ying Zhang 2,  Xinsheng Lei 1,  Yingxia Li 4,  Xun Huang 5,  Zonglong Chen 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China.
  • 3 Lingang Laboratory, Shanghai, 200031, China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: liyx417@fudan.edu.cn.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China; School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China. Electronic address: xhuang@lglab.ac.cn.
  • 6 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: zlchen19@fudan.edu.cn.
PMID: 41713323 DOI: 10.1016/j.ejmech.2026.118646
Abstract

Histone acetylation, catalyzed by histone acetyltransferases (HATs), is a critical post-translational modification that regulates diverse cellular processes. p300/CBP, an important family of HATs, has emerged as promising targets for Cancer therapy. Herein, we report a series of novel p300 HAT inhibitors based on the lead compound CPI-1612 through structure-based drug design. Among these, compound B6, featuring an imidazo[4,5-b]pyridine-2-one fused-ring scaffold, demonstrates potent in vitro inhibitory activity, with IC50 values of 7 nM against the p300 HAT domain and 8.8 nM in multiple myeloma OPM-2 cells. Treatment with compound B6 suppressed c-Myc expression and decreased H3K18ac/H3K27ac levels in OPM-2 and 22RV1 cells. Furthermore, oral administration of B6 (20 mg/kg) significantly suppressed tumor growth in the OPM-2 xenograft mouse model, achieving a tumor growth inhibition of 60%. Metabolite profiling of B6 provided key insights to guide further rational structural optimization aimed at improving its metabolic stability. Collectively, these findings identify B6 as a highly potent and orally active p300 HAT inhibitor, underscoring its potential as a lead compound for further Anticancer drug development.

Keywords

Antitumor; Histone acetyltransferases; Structural optimization; Structure-based drug design; p300/CBP inhibitors.

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