Insight into the inhibitor discrimination by FLT3 F691L.

Fms-like tyrosine kinase 3 (FLT3) belongs to the receptor tyrosine kinase family and expressed in hematopoietic progenitor cells. FLT3 gene mutations are reported in ~30% of acute myeloid leukemia cases. FLT3 kinase domain mutation F691L is one of the common causes of acquired resistance to the FLT3 inhibitors including quizartinib. MZH29 and crenolanib were previously reported to inhibit FLT3 F691L. However, crenolanib was reported for the moderate inhibition. We found that Glu661and Asp829 were the most significant residues to target the FLT3 F691L which contribute most significantly to the binding energy with MZH29 and crenolanib. These interactions were found absent with quizartinib. Further free energy landscape analysis revealed that FLT3 F691L bound to MZH29 and crenolanib was more stable as compared to quizartinib.