Crenolanib - FLT3
Fms-related tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) with important roles in hematopoietic stem/progenitor cell survival and proliferation. FLT3 belongs to the class III RTK family, including Fms, c-KIT, PDGFRα, and PDGFRβ. The human FLT3 gene is located on chromosome 13q12 and contains 24 exons. It encodes a membrane- bound glycosylated protein of 993 amino acids with a molecular weight of 158-160 kDa, as well as a non-glycosylated isoform of 130-143 kDa that is not associated with the plasma membrane.
Role of FLT3 in AML
Mutations in FLT3 are implicated in up to 35% of acute myeloid leukemia (AML) cases. Two major classes of activating FLT3 mutations have been identified in AML patients: internal-tandem duplications (ITDs) and tyrosine kinase domain (TKD) point mutations. These mutations cause FLT3 to be constitutively active (i.e. independent of its ligand) which leads to aberrant activation of multiple downstream pathways such as PI3K/AKT, MAPK/ERK, and STAT5. FLT3 mutations are now recognized as the key activating mechanism in a subset of AML and are thus a target for therapy. In addition, AML with mutated FLT3 is associated with poor clinical outcomes, thus emphasizing the need for a FLT3-targeted tyrosine kinase inhibitor (TKI).
Preclinical Trials Have Shown Crenolanib to be Active in Inhibiting Both Wild-Type and Mutant FLT3
Crenolanib is cytotoxic to the FLT3/ITD-expressing leukemia cell lines Molm14 and MV411, with IC50s of 7 nM and 8 nM, respectively. In immunoblots, crenolanib inhibited phosphorylation of both the wild-type FLT3 receptor (in SEMK2 cells) and the FLT3/ITD receptor (in Molm14 cells) in culture medium with IC50s of 1-3 nM. Importantly, the IC50 of crenolanib against the D835Y mutated form of FLT3 was 8.8 nM in culture medium. Furthermore, crenolanib had cytotoxic activity against primary samples that were obtained from patients who had developed D835 mutations while receiving FLT3 TKIs. In vitro, the IC50 of crenolanib for inhibition of FLT3/ITD in plasma was found to be 34 nM, indicating a relatively low degree of plasma protein binding. From pharmacokinetic studies of crenolanib in solid tumor patients, steady state trough plasma levels of roughly 500 nM were found to be safe and tolerable, suggesting that crenolanib could potentially inhibit the target in vivo. Crenolanib has no significant activity against c-KIT, which may be an advantage in that myelosuppression can be avoided.1 Furthermore, there was no evidence of QTc prolongation in patients treated with crenolanib. In summary, crenolanib offers a number of advantages over other FLT3 TKIs. Clinical trials of crenolanib in AML patients with FLT3 activating mutations are being planned.
1Galanis et al. Cancer Res. 2012; 72:3660