Design and synthesis of selective FLT3 inhibitors via exploration of back pocket II

Aim: The clinical benefits of FLT3 inhibitors against acute myeloid leukemia (AML) have been limited by selectivity and resistance mutations. Thus, to identify FLT3 inhibitors possessing high selectivity and potency is of necessity. Methods & results: The authors used computational methods to systematically compare pocket similarity with 269 kinases. Subsequently, based on these investigations and beginning with in-house compound 10, they synthesized a series of 6-methyl-isoxazol[3,4-b]pyridine-3-amino derivatives and identified that compound 45 (IC50: 103 nM) displayed gratifying potency in human AML cell lines with FLT3-internal tandem duplications mutation as well as FLT3-internal tandem duplications-tyrosine kinase domain-transformed BaF3 cells. Conclusion: The integrated biological activity results indicated that compound 45 deserves further development for therapeutic remedies for AML.

Automated summary

This study used computational methods to compare pocket similarity among 269 kinases, and then synthesized a series of 6-methyl-isoxazol[3,4-b]pyridine-3-amino derivatives based on these investigations. Compound 45 displayed potent inhibitory activity against FLT3 internal tandem duplications mutation and FLT3 internal tandem duplications-tyrosine kinase domain-transformed BaF3 cells. The integrated biological activity results suggest that compound 45 deserves further development as a therapeutic remedy for AML.