Discovery of a novel 1H-pyrazole-3-amine derivative 6h with potent antitumor activity by targeting tubulin and FLT3.

Authors

Bao-Kai Dou, Xiang-Yu Ma, Xiao-Fen Zhang, Ying-Jie Cui

Published in

European journal of medicinal chemistry. Volume 318. Pages 119211. Aug 08, 2026. Epub Aug 08, 2026.

Abstract

A novel series of 1H-pyrazole-3-amine derivatives was designed, synthesized, and their antitumor activities were evaluated. Among them, 6h showed potent antiproliferative activity against solid tumor cell lines and leukemia cell lines, with IC₅₀ values ranging from 3.3 to 25.0 nM. Mechanism studies revealed that 6h could effectively inhibit microtubule polymerization (IC₅₀ = 3.6 μM) via targeting the colchicine binding site and disrupted cellular microtubule networks. Notably, the preliminary kinase selectivity results showed 6h displayed selectivity for FLT3 kinase (IC₅₀ = 58.6 nM) over other kinases screened, including the homologous c-KIT. Western blot analysis demonstrated that 6h inhibited the phosphorylation of FLT3 and its downstream signaling mediator STAT5 in MOLM-13 cells. 6h could induce tumor cell cycle arrest and apoptosis. Furthermore, in a MOLM-13 xenograft model, 6h at the dosage of 30 mg/kg exhibited effective antitumor activity without notable body-weight loss and the major organ damage. Pharmacokinetic evaluation of 6h in rats revealed an oral bioavailability of 5.6 %. Molecular docking and dynamics simulations supported stable binding modes of 6h with both tubulin and FLT3. Collectively, these results suggested that 6h could be regarded as a promising lead compound against tubulin and FLT3 for further investigation.

PMID:
42571759
Bibliographic data and abstract were imported from PubMed on 10 Aug 2026.

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