Design, synthesis and pharmacological characterization of aminopyrimidine derivatives as BTK/FLT3 dual-target inhibitors against acute myeloid leukemia

Fansheng Ran; Yun Liu; Jian Zhu; Xuexian Deng; Hongmei Wu; Weizhi Tao; Xudong Xie; Yirong Hu; Yanan Zhang; Yong Ling

doi:10.1016/j.bioorg.2023.106479

Design, synthesis and pharmacological characterization of aminopyrimidine derivatives as BTK/FLT3 dual-target inhibitors against acute myeloid leukemia

Bioorg Chem. 2023 May:134:106479. doi: 10.1016/j.bioorg.2023.106479. Epub 2023 Mar 13.

Authors

Fansheng Ran¹, Yun Liu², Jian Zhu², Xuexian Deng², Hongmei Wu², Weizhi Tao², Xudong Xie², Yirong Hu², Yanan Zhang³, Yong Ling⁴

Affiliations

¹ School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, China; Nantong Key Laboratory of Small Molecular Drug Innovation, School of Pharmacy, Nantong University, Nantong 226001, China.
² School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, China.
³ School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, China; Nantong Key Laboratory of Small Molecular Drug Innovation, School of Pharmacy, Nantong University, Nantong 226001, China. Electronic address: yznj00@outlook.com.
⁴ School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, China; Nantong Key Laboratory of Small Molecular Drug Innovation, School of Pharmacy, Nantong University, Nantong 226001, China. Electronic address: Lyyy111@sina.com.

PMID: 36989958
DOI: 10.1016/j.bioorg.2023.106479

Abstract

A novel class of aminopyrimidine-based Bruton's tyrosine kinase (BTK) and FMS-like tyrosine kinase 3 (FLT3) dual-target inhibitors based on the BTK inhibitor spebrutinib was designed for the treatment of acute myeloid leukemia. Representative compounds 14d, 14g, 14j and 14m effectively inhibited BTK, FLT3, and FLT3(D835Y) mutant activities with low nanomolar IC₅₀'s. These compounds displayed potent antiproliferative activities against leukemia cells with IC₅₀'s of 0.29-950 nM. In particular, 14m had IC₅₀ values 101-1045 times lower than those of spebrutinib against all cancer cell lines tested. Compound 14m effectively induced autophagy and apoptosis in MV-4-11 cells through regulating related proteins in a dose-dependent manner. Finally, intraperitoneal administration of 14m at 20 mg/kg significantly repressed the growth of MV-4-11 cells with a TGI value of 95.68% with no apparent toxicity. These BTK/FLT3 dual-target inhibitors represent promising leads for further structural optimization and antitumor mechanism studies.

Keywords: Acute myeloid leukemia; Autophagy; Bruton’s tyrosine kinase (BTK); Dual-target inhibitors; FMS-like tyrosine kinase 3 (FLT3).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Agammaglobulinaemia Tyrosine Kinase
Antineoplastic Agents* / chemistry
Apoptosis
Cell Line, Tumor
Cell Proliferation
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / metabolism
Protein Kinase Inhibitors / chemistry
Pyrimidines / chemistry
fms-Like Tyrosine Kinase 3

Substances

spebrutinib
2-aminopyrimidine
Pyrimidines
Agammaglobulinaemia Tyrosine Kinase
Protein Kinase Inhibitors
Antineoplastic Agents
FLT3 protein, human
fms-Like Tyrosine Kinase 3