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

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 

机构地区：[1]Key Laboratory of Structure-Based Drug Design and Discovery,Ministry of Education,Shenyang Pharmaceutical University,Shenyang 110016,China [2]Department of Pharmacology,Shenyang Pharmaceutical University,Shenyang 110016,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第8期3605-3623,共19页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.82173685 and No.82073320);Chinese Pharma-ceutical Association-Yi ling Biomedical Innovation Fund(No.CPAYLJ202001,China);Liao Ning Revitalization Talents Program(No.XLYC2002115,China);Key R&D Plan of Liaoning Province in 2020(No.2020020215-JH2/103,China);Development Project of Ministry of Education Innovation Team(No.IRT1073,China);Natural Science Foundation of Shenyang(22-315-6-11,China).

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 identified 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 engagement 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 revealed that 37 possessed tolerable properties(t_(1/2)=1.93±0.91 h,F=97.2%)after intraperitoneal administration in rats.Mechanism study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling pathway.Moreover,analysis 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.

关 键 词：DOT1L R231Q mutation Lung cancer Adenosine-containing inhibitors EPIGENETICS 

分 类 号：R96[医药卫生—药理学]