Design and In Silico Evaluation of Tjipanazole Analogues as Dual Chk1 and FLT3 Inhibitors for Targeted AML Therapy

ABSTRACT

This study reports an in silico design and molecular docking analysis of a novel series of Tjipanazole (TPZ) analogues aimed at dual inhibition of checkpoint kinase 1 (Chk1) and Fms‐like tyrosine kinase 3 (FLT3), two pivotal targets implicated in the pathogenesis of acute myeloid leukemia. Three distinct molecular series of unsubstituted Tjipanazole (TPZ), mono‐chloro TPZ, and di‐chloro TPZ analogues were evaluated for their binding affinities, interaction patterns, and binding orientations relative to known inhibitors. Among the designed analogues, Octyl TPZ (from Series 1), Chlorohexyl TPZ (from Series 2), and Dichloro Propyl TPZ (from Series 3) exhibited better binding affinities compared to reference ligands UCN‐01 and gilteritinib (C6F), demonstrating significant engagement through critical interactions with functionally important residues at the active sites of both targets. ADMET profiling identified challenges with solubility and permeability. These findings support the potential of Tjipanazole analogues from the structure‐based perspective as promising dual‐target modulators that require further optimization and binding stability evaluations for further biological validation.