Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations

The use of covalent irreversible
binding inhibitors is an established
concept for drug development. Usually, the discovery of new irreversible
kinase inhibitors occurs serendipitously, showing that efficient rational
approaches for the rapid discovery of new drugs are needed. Herein,
we report a virtual screening strategy that led to the discovery of
irreversible inhibitors of FMS-like tyrosine kinase 3 (FLT3) involved
in the pathogenesis of acute myeloid leukemia. A virtual screening
library was designed to target the highly conserved Cys828 residue
preceding the DFG motif by modification of reported reversible inhibitors
with chemically reactive groups. Prospective covalent docking allowed
the identification of two lead series, resulting in a massive increase
in inhibition of kinase activity and cell viability by irreversible
inhibitors compared to the corresponding reversible scaffolds. Lead
compound 4b (BSc5371) displays superior cytotoxicity
in FLT3-dependent cell lines to compounds in recent clinical trials
and overcomes drug-resistant mutations.