Rapid Identification of a Potent, Selective, and Orally Active p300/CBP Bromodomain Inhibitor Bearing an Imidazo[1,2-a]pyridine Scaffold via a Highly Efficient Four-Step Synthesis.

Authors

Zonglong Chen, Ying Zhang, Zihan Li, Hui Shen, Hanqi Wang, Hong Yang, Cheng Zhang, Jiankang Hu, Yujie Wang, Qiongyu Shi, Yan Zhang, Jian Ding, Yanfen Fang, Yong Xu, Xun Huang, Yingxia Li

Published in

Journal of medicinal chemistry. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

E1A-binding protein (p300)/CREB-binding protein (CBP) bromodomains represent attractive therapeutic targets for anticancer drug development. Herein, we describe a structure-guided optimization of the lead compound UMB298 through a conformationally constrained cyclization strategy. A concise four-step synthesis (overall yield >30%), centered on a three-component reaction, was developed, enabling efficient construction of a lactam-containing imidazo[1,2-a]pyridine library for rapid screening. Among these compounds, CZL-105 emerges as a promising p300/CBP bromodomain inhibitor. It exhibits potent activity against p300 and CBP while sparing BET and demonstrates strong antiproliferative potency in OPM-2 multiple myeloma cells. Acceptable metabolic stability and pharmacokinetics support once-daily oral dosing, leading to significant tumor growth inhibition (TGI = 61%) in an OPM-2 xenograft model. These results position CZL-105 as a promising lead compound for further development. This work combines a rational design strategy and efficient chemical synthesis, accelerating the discovery of novel p300/CBP bromodomain inhibitors.

PMID:
42467465
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.

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