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Insight into the inhibitor discrimination by FLT 3 F691L
Author(s) -
Verma Sharad,
Singh Aditi,
Kumari Anchala,
Pandey Bharati,
Jamal Salma,
Goyal Sukriti,
Sinha Siddharth,
Grover Abhinav
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13169
Subject(s) - myeloid leukemia , cancer research , tyrosine kinase , protein kinase domain , tyrosine kinase inhibitor , chemistry , receptor tyrosine kinase , kinase , pharmacology , gene , biology , receptor , genetics , biochemistry , cancer , mutant
Fms‐like tyrosine kinase 3 ( FLT 3) belongs to the receptor tyrosine kinase family and expressed in hematopoietic progenitor cells. FLT 3 gene mutations are reported in ~30% of acute myeloid leukemia cases. FLT 3 kinase domain mutation F691L is one of the common causes of acquired resistance to the FLT 3 inhibitors including quizartinib. MZH 29 and crenolanib were previously reported to inhibit FLT 3 F691L. However, crenolanib was reported for the moderate inhibition. We found that Glu661and Asp829 were the most significant residues to target the FLT 3 F691L which contribute most significantly to the binding energy with MZH 29 and crenolanib. These interactions were found absent with quizartinib. Further free energy landscape analysis revealed that FLT 3 F691L bound to MZH 29 and crenolanib was more stable as compared to quizartinib.