Discovery and rational design of 2-aminopyrimidine-based derivatives targeting Janus kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3)

Abstract

Herein, with the help of computer-aided drug design (CADD), we describe the structure-based rational drug design, structure-activity relationships, and synthesis of a series of 2-aminopyrimidine derivatives that inhibit both JAK2 and FLT3 kinases. These screening cascades revealed that compound 14l demonstrated the most inhibitory activity with IC₅₀ values of 1.8 and 0.68 nM against JAK2 and FLT3 respectively. 14l also showed potent anti-proliferative activities against HEL (IC₅₀ = 0.84 μM) and Molm-13 (IC₅₀ = 0.019 μM) cell lines, but relatively weak cytotoxicity against K562 and PC-3 cell lines, which proved that it might have high target specificity. In vitro metabolism assay, 14l exhibited moderate stability in RLM (Rat Liver Microsomes) with a half-life time of 31 min. In the cellular context of Molm-13, 14l induced cell cycle arrest in G₁/S phase and enhanced apoptosis in a dose-dependent manner. These results indicate that 14l is a promising dual JAK2/FLT3 inhibitor and worthy of further development.

Keywords: 2-Aminopyrimidine derivatives; JAK2/FLT3 dual inhibitor; Structure–activity relationships.