Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors

Abstract

A series of 4-arylamido 5-methylisoxazole derivatives with quinazoline core was designed and synthesised based on conformational rigidification of a previous type II FMS inhibitor. Most of quinazoline analogues displayed activity against FLT3 and FLT3-ITD. Compound 7d, 5-methyl-N-(2-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide, exhibited the most potent inhibitory activity against FLT3 (IC 50 ¼ 106 nM) with excellent selectivity profiles over 36 other protein kinases including cKit and FMS kinase. Compound 7d was also active in FLT-ITD, with an IC 50 value of 301 nM, and other FLT3 mutants showing potential as an AML therapeutics.

Rational design and synthesis of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazole derivatives as inhibitors targeting FMS-like tyrosine kinase 3 (FLT3) and its mutants

“…On the other hand, FMS kinase has a Thr663 residue in the same sequence at the active site. Therefore, compound 8r could not form a π-π interaction with Thr663, which explains its selective inhibition between FLT3 and FMS kinase 21 . The positively charged nitrogen of the ethyl piperazine ring forms a π-cation interaction with His809.…”

“…We found that core structures including benzimidazole and quinazoline play a key role in retaining their binding mode that interacts with the Phe691 residue in FLT3 kinase via π-π interaction by means of investigating molecular docking. On the process of structure optimisation to enhance activity, it was verified that indazole fragment could be employed as a hinge binder that binds with the ATP-binding pocket 21 ( Figure 3 ). Based on this observation, we replaced the isoxazole structure with various phenyl amide groups retaining its quinazoline core structure first and synthesised several derivatives, including 5-methylisoxazole-4-carboxamide and 3–(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamide, which were considered as starting points to develop novel FLT3 inhibitors.…”

“…In our previous study, benzimidazole and quinazoline derivatives were synthesised and optimised from FMS inhibitors as selective type II FLT3 inhibitors 20 , 21 . We found that core structures including benzimidazole and quinazoline play a key role in retaining their binding mode that interacts with the Phe691 residue in FLT3 kinase via π-π interaction by means of investigating molecular docking.…”