FLT3 INHIBITORS: RECENT ADVANCES AND PROBLEMS FOR CLINICAL APPLICATION

Abstract

FLT3, a type III receptor tyrosine kinase, expresses on most acute leukemia cells as well as normal hematopoietic stem/progenitor cells. Mutation in the FLT3 gene is the most frequent genetic alteration in acute myeloid leukemia (AML) and is well known as an important driver mutation for the development of myeloid malignancies. FLT3 mutation is a strong poor prognostic factor for the long-term survival in AML patients, while neither high-dose chemotherapy nor allogeneic hematopoietic stem cell transplantation can overcome a poor prognosis. Development of an FLT3 inhibitor is, therefore, much awaited. To date, several potent FLT3 inhibitors have been developed and some of them were evaluated for efficacy in clinical trials, although no FLT3 inhibitor has been yet approved. Moreover, several problems for clinical use, such as adverse effects, blood concentration and resistance have been apparent. Recently developed AC220 is a highly selective and sensitive FLT3 inhibitor. In Phase I and II trials, AC220 so far showed the best efficacy of AML cells harboring FLT3 mutation among clinically evaluated FLT3 inhibitors, while severe bone marrow suppression and QTc prolongation should be resolved for the clinical use. In this review, I summarize the characteristics of FLT3 inhibitors in clinical development and discuss important issues to be resolved for clinical use.

Keywords: FLT3; inhibitors; leukemia; molecular target; resistance.

Fig. 1

FLT3 mutations. There are two types of FLT3 mutations, FLT3-ITD and FLT3-KDM. FLT3-ITD occurs between exons 14 and 15. When leukemia cells have FLT3-ITD, PCR products give a wild-type band and a larger ITD band (A). D835 and I836 codons are encoded by the nucleotide GATATC which forms the Eco RV restriction site. The amplified products of wild type FLT3 are digested to two bands by the Eco RV. When amplified products contain D835-mutations (FLT3-KDM), undigested bands are observed (B).

Fig. 2

Structure and inhibitory activity of FLT3 inhibitors. Tandutinib, Lestaurtinib and Midostaurin are first-generation FLT3 inhibitors. The second-generation FLT3 inhibitors, Sorafenib and Quizartinib, show clinical efficacy, while several problems regarding adverse effects and resistant mutations should be resolved before clinical use. Crenolanib is a recently developed FLT3 inhibitor, which is potent against both FLT3-ITD and FLT3-KDM.

Fig. 3

Structure of FLT3 and resistant mutations. In the inactive form of wild-type FLT3, the JM domain blocks activation of the kinase and may inhibit self-dimerization. Mutations of D835 and Y842 residues in the A-loop induce a conformational change blocking the binding of FLT3 inhibitors to the ATP-binding-pocket. Since the F691 residue is a gatekeeper of the ATP-binding-pocket, its mutation also blocks the binding of FLT3 inhibitors.