Docking-guided exploration of the anti-flt3 potential of isoindigo derivatives towards potential treatments of acute myeloid leukemia

Abstract

FMS-like tyrosine kinase 3 (Flt3) is an oncogenic kinase implicated in leukemia, with its primary association being acute myeloid leukemia (AML). Flt3-specific inhibitors have demonstrated promising outcomes in disrupting AML progression. While isoindigo derivatives, e.g., meisoindigo, have proven effective against chronic myeloid leukemia, their structural resemblance to indirubin derivatives, known for potent anti-Flt3 bioactivities, does not guarantee similar effects. In fact, meisoindigo and other related derivatives have been reported to exhibit limited or no anti-Flt3 bioactivities. This observation prompted us to explore the anti-Flt3 profile of novel isoindigo derivatives. Employing docking studies on both wild-type and mutated active Flt3, we synthesized a series of isoindigo derivatives and assessed their Flt3 inhibitions. Nine derivatives displayed low micromolar and submicromolar IC₅₀ values. The most potent derivative achieved an IC₅₀ of 88 nM against the mutant Flt3D835Y. Intriguingly, the same compound showed an anti-RET kinase IC₅₀ of 57 nM, reminiscent of the dual Flt3/RET inhibitory profiles of indirubin derivatives. Cell-based bioassays further revealed that these derivatives exhibited submicromolar selective toxicities against HL-60 human leukemia cells, which overexpress Flt3. In contrast, no cytotoxic effects were observed on HCT-116 colon cancer cells, MCF-7 breast cancer cells, or normal fibroblasts, all known to lack Flt3 expression.