Discovery of first-in-class DOT1L inhibitors against the R231Q gain-of-function mutation in the catalytic domain with therapeutic potential of lung cancer

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外文摘要：Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung cancer.Herein,a series of adenosine-containing derivatives were iden-tified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q cell.The most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation,self-renewal,migration,and invasion of lung cancer cell lines at low micromolar concentrations.The cell permeability and cellular target engage-ment of 37 were verified by both CETSA and DARTS assays.In the H460R231Q OE cell-derived xenograft(CDX)model,37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks(TGI=54.38％),without obvious toxicities.A pharmacokinetic study re-vealed that 37 possessed tolerable properties(t1/2=1.93±0.91 h,F=97.2％)after intraperitoneal administration in rats.Mechanism study confirmed that 37 suppressed malignant phenotypes of lung can-cer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling pathway.Moreover,anal-ysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the"Induced-fit"allosteric model in favor to the discovery of potent DOT1L candidates.

外文关键词：

DOT1LR231Q mutationLung cancerAdenosine-containing inhibitorsEpigenetics

作者：

Zehui Tan、Ning Guo、Zhi Cao、Shuyu Liu、Jiayu Zhang、Deyi Ma、Jiahao Zhang、Wencai Lv、Nan Jiang、Linghe Zang、Lihui Wang、Xin Zhai

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作者单位：

Key Laboratory of Structure-Based Drug Design and Discovery,Ministry of Education,Shenyang Pharmaceutical University,Shenyang 110016,China

Department of Pharmacology,Shenyang Pharmaceutical University,Shenyang 110016,China

基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaChinese Pharmaceutical Association-Yi ling Biomedical Innovation Fund,ChinaLiao Ning Revitalization Talents Program,ChinaKey R&D Plan of Liaoning Province in 2020,ChinaDevelopment Project of Ministry of Education Innovation Team,ChinaNatural Science Foundation of Shenyang,China

项目编号：

8217368582073320CPAYLJ202001XLYC20021152020020215-JH2/103IRT107322-315-6-11

出版年：

2024

DOI：

10.1016/j.apsb.2024.03.018

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(8)