Discovery of 5-trifluoromethyl-2-aminopyrimidine derivatives as potent dual inhibitors of FLT3 and CHK1

Minjie Deng; Yue Gao; Peipei Wang; Wenjing Du; Gaoya Xu; Jia Li; Yubo Zhou; Tao Liu

doi:10.1039/d3md00597f

Discovery of 5-trifluoromethyl-2-aminopyrimidine derivatives as potent dual inhibitors of FLT3 and CHK1

RSC Med Chem. 2023 Dec 7;15(2):539-552. doi: 10.1039/d3md00597f. eCollection 2024 Feb 21.

Authors

Minjie Deng¹, Yue Gao^{2

3}, Peipei Wang^{2

3}, Wenjing Du¹, Gaoya Xu^{2

3}, Jia Li^{2

3

4

5}, Yubo Zhou^{3

5}, Tao Liu^{1

6

7}

Affiliations

¹ ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University Zijingang Campus Hangzhou 310058 P.R. China lt601@zju.edu.cn.
² School of Chinese Materia Medica, Nanjing University of Chinese Medicine Nanjing 210023 P.R. China.
³ State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 P.R. China ybzhou@simm.ac.cn.
⁴ Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery Yantai 264117 P.R. China.
⁵ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Zhongshan 528400 P.R. China.
⁶ Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, Zhejiang University Hangzhou 310058 P.R. China.
⁷ National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University Hangzhou 310058 P.R. China.

PMID: 38389894
PMCID: PMC10880922 (available on 2024-12-07)
DOI: 10.1039/d3md00597f

Abstract

Here, we discover an FLT3/CHK1 dual inhibitor (30) that exhibits excellent kinase potency and antiproliferative activity against MV4-11 cells. Simultaneously, 30 possesses high selectivity over c-Kit enzyme and low hERG inhibitory ability. Compound 30, meanwhile, overcomes varied resistance in BaF3 cell lines carrying FLT3-TKD and FLT3-ITD mutations. Moreover, 30 demonstrates favorable oral PK properties and kinase selectivity. These conclusions support that compound 30 may be a promising potential FLT3/CHK1 dual agent for further development.