Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants.
Mutations of the type III receptor tyrosine kinase FLT3 occur in approximately 30% of acute myeloid leukemia patients and lead to constitutive activation. This has made FLT3-activating mutations an attractive drug target because they are probable driver mutations of this disease. As more potent FLT3 inhibitors are developed, a predictable development of resistance-conferring point mutations, commonly at residue D835, has been observed. Crenolanib is a highly selective and potent FLT3 tyrosine kinase inhibitor (TKI) with activity against the internal tandem duplication (FLT3/ITD) mutants and the FLT3/D835 point mutants. We tested crenolanib against a panel of D835 mutant cell lines and primary patient blasts and observed superior cytotoxic effects when compared with other available FLT3 TKIs such as quizartinib and sorafenib. Another potential advantage of crenolanib is its reduced inhibition of c-Kit compared with quizartinib. In progenitor cell assays, crenolanib was less disruptive of erythroid colony growth, which may result in relatively less myelosuppression than quizartinib. Finally, correlative data from an ongoing clinical trial demonstrate that acute myeloid leukemia patients can achieve sufficient levels of crenolanib to inhibit both FLT3/ITD and resistance-conferring FLT3/D835 mutants in vivo. Crenolanib is thus an important next-generation FLT3 TKI.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD;
Allison
A
Galanis
Hayley
H
Ma
Trivikram
T
Rajkhowa
Abhijit
A
Ramachandran
Donald
D
Small
Jorge
J
Cortes
Mark
M
Levis
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D003114:Colony-Forming Units Assay; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D017354:Point Mutation; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D010880:Piperidines; D013778:Tetrazolium Salts; D013844:Thiazoles; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3; C022616:thiazolyl blue; C577197:crenolanib