2. Academic Validation
  3. Discovery and structure - activity relationship exploration of pyrazolo[1,5-a]pyrimidine derivatives as potent FLT3-ITD inhibitors

Discovery and structure - activity relationship exploration of pyrazolo[1,5-a]pyrimidine derivatives as potent FLT3-ITD inhibitors

  • Bioorg Med Chem. 2021 Oct 15;48:116422. doi: 10.1016/j.bmc.2021.116422.
Yun Chen 1,  Gang Bai 2,  Yan Li 2,  Yi Ning 2,  Sufen Cao 3,  Jinpei Zhou 4,  Jian Ding 2,  Huibin Zhang 5,  Hua Xie 6,  Wenhu Duan 7
Affiliations

Affiliations

  • 1 Division of Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
  • 3 Division of Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 5 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: [email protected].
  • 6 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; Zhongshan Institute for Drug Discovery, the Institutes of Drug Discovery and Development, Chinese Academy of Sciences, Zhongshan 528400, PR China. Electronic address: [email protected].
  • 7 Division of Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China. Electronic address: [email protected].
PMID: 34583130 DOI: 10.1016/j.bmc.2021.116422
Abstract

Internal tandem duplications of FLT3 (FLT3-ITD) occur in approximately 25% of all acute myeloid leukemia (AML) cases and confer a poor prognosis. Optimization of the screening hit 1 from our in-house compound library led to the discovery of a series of pyrazolo[1,5-a]pyrimidine derivatives as potent and selective FLT3-ITD inhibitors. Compounds 17 and 19 displayed potent FLT3-ITD activities both with IC50 values of 0.4 nM and excellent antiproliferative activities against AML cell lines. Especially, compounds 17 and 19 inhibited the quizartinib resistance- conferring mutations, FLT3D835Y, both with IC50 values of 0.3 nM. Moreover, western blot analysis indicated that compounds 17 and 19 potently inhibited the phosphorylation of FLT3 and attenuated downstream signaling in AML cells. These results indicated that pyrazolo[1,5-a]pyrimidine derivatives could be promising FLT3-ITD inhibitors for the treatment AML.

Keywords

5-a]pyrimidine; Acute myeloid leukemia; FLT3; FLT3-ITD; Pyrazolo[1; Structure–activity relationships.

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