Structure-guided design of 7-azaindole DNMT1 inhibitors active against hypomethylating agent–resistant acute myeloid leukemia
Abstract
Pharmacological reversal of abnormal promoter DNA hypermethylation at tumor suppressor genes (TSGs) is a key therapeutic paradigm for cancer management. However, the clinical efficacy of currently approved nucleoside analog hypomethylating agents (HMAs) is limited by dose-dependent toxicity and high resistance rates. Nonnucleoside, DNA methyltransferase 1 (DNMT1)-selective inhibitors offer a promising alternative. To date, only limited chemotypes, exemplified by the dicyanopyridine derivative GSK3685032 (GSK5032), have demonstrated translatable DNMT1 inhibition, with resistance emerging upon prolonged exposure. To address these limitations, we employ structure-guided scaffold hopping and chemical optimization to develop a series of DNMT1 inhibitors (DNMT1i) featuring a bicyclic 7-azaindole scaffold. We identify DMI46, a potent enzymatic DNMT1i capable of reversing cancer-specific DNA methylation abnormalities and TSG silencing, leading to robust antileukemic effects and favorable tolerability. Cryoelectron microscopy (cryo-EM) studies reveal that the 7-azaindole inhibitor exhibits enhanced intercalation into hemi-methylated CpG dyads and increased minor-groove contacts within the DNMT1/hemimethylated DNA complex compared to GSK5032. These structural features enable sustained DNMT1 targeting and significant antiproliferative activity of DMI46 in GSK5032-resistant acute myeloid leukemia (AML) cells. We also demonstrate DMI46’s capacity to overcome AML resistance to nucleoside-based HMAs both in vitro and in vivo. These findings introduce a distinct DNMT1i chemotype with enhanced on-target engagement and broad applicability against HMA-resistant AML.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Shibing Tang
Institute of Drug Discovery, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Liangyi Zong
Institute of Drug Discovery, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Shuyuan Ma
Key Laboratory of Glyco-drug Research of Zhejiang Province, School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences
Yini Shang
Institute of Drug Discovery, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Jiale Wei
Key Laboratory of Glyco-drug Research of Zhejiang Province, School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences
Jianguang Liu
Institute of Drug Discovery, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Ying Cui
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine
Huahui Guo
Institute of Drug Discovery, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Kang Zou
Institute of Drug Discovery, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Kezhi Wang
Institute of Drug Discovery, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Hongkun Li
Key Laboratory of Glyco-drug Research of Zhejiang Province, School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences
Fei Ye
Jing Huang
Cheng Luo
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine
Zhihai Li
Key Laboratory of Glyco-drug Research of Zhejiang Province, School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences
Stephen B. Baylin
Xiangqian Kong
Institute of Drug Discovery, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences