Optimization of a Series of Novel 1H-Pyrrolo[3,2-c]pyridine-Based USP1 Inhibitors with Potent In Vivo Antitumor Activity.

Authors

Tao Yang, Xue Cui, Qingyan Li, Yaxin Teng, Minghai Tang, Xinyu Zou, Xiaobo Cen, Lijuan Chen, Min Zhao, Linyu Yang, Zhuang Yang

Published in

Journal of medicinal chemistry. Volume 69. Issue 17. Pages 20403-20432. Sep 10, 2026.

Abstract

USP1, a deubiquitinating enzyme critical for DNA damage repair, represents a promising therapeutic target for cancers. In this study, we employed scaffold hopping to design and synthesize a series of 1H-pyrrolo[3,2-c]pyridine-based USP1 inhibitors. Among these, the lead compound 38a displayed robust enzymatic and cellular potencies. 38a dose-dependently induced Ub-PCNA accumulation, triggered cell cycle arrest, and potently suppressed cell viability. Additionally, 38a synergized with olaparib in MDA-MB-463 cells. Uniquely, 38a effectively induced c-MYC downregulation. In vivo studies confirmed 38a's favorable oral bioavailability. In the MDA-MB-436 xenograft model, the combination of 38a with olaparib exerted potent antitumor efficacy, with a tumor inhibition rate of 80.7%, and the antitumor activity of 38a stemmed from USP1 inhibition. Furthermore, in the DLBCL PDX model with high c-MYC expression, 38a demonstrated efficacy comparable to standard first-line therapies. Preliminary safety evaluation confirmed the safety profile of 38a. Taken together, 38a is a highly promising antitumor lead compound with great translational potential.

PMID:
42720480
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

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