TY - JOUR
T1 - Crenolanib is a potent inhibitor of flt3 with activity against resistance-Conferring point mutants
AU - Galanis, Allison
AU - Ma, Hayley
AU - Rajkhowa, Trivikram
AU - Ramachandran, Abhijit
AU - Small, Donald
AU - Cortes, Jorge
AU - Levis, Mark
PY - 2014/1/2
Y1 - 2014/1/2
N2 - 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.Wetested 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. This study is registered at clinicaltrials.gov (ID: NCT01657682). (Blood. 2014;123(1):94-100).
AB - 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.Wetested 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. This study is registered at clinicaltrials.gov (ID: NCT01657682). (Blood. 2014;123(1):94-100).
UR - http://www.scopus.com/inward/record.url?scp=84891814607&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84891814607&partnerID=8YFLogxK
U2 - 10.1182/blood-2013-10-529313
DO - 10.1182/blood-2013-10-529313
M3 - Article
C2 - 24227820
AN - SCOPUS:84891814607
SN - 0006-4971
VL - 123
SP - 94
EP - 100
JO - Blood
JF - Blood
IS - 1
ER -