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Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants.

Abstract：

: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.

journal_name

Blood

journal_title

Blood

authors

Galanis A,Ma H,Rajkhowa T,Ramachandran A,Small D,Cortes J,Levis M

doi

10.1182/blood-2013-10-529313

subject

Has Abstract

pub_date

2014-01-02 00:00:00

pages

94-100

issue

1

eissn

0006-4971

issn

1528-0020

pii

blood-2013-10-529313

journal_volume

123

pub_type

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