Crenolanib

Crenolanib (CP-868596) is a potent, selective PDGFR/Flt-3 inhibitor with Ki of 3.2, 2.1 and 0.74 nM for wild-type PDGFRα, PDGFRβ and FLT3, respectively; displays >100-fold more selective for PDGFR than c-Kit, VEGFR-2, TIE-2, FGFR-2, EGFR, erbB2, and Src; also is a potent inhibitor of PDGFRα D842V-mutant kinase with IC50 of 10 nM, significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRA kinases (D842I, D842V, D842Y, DI842-843IM, and deletion I843) ; Crenolanib is active against models of drug-resistant FLT3-ITD-positive AML.Blood Cancer Phase 3 Clinical (In Vitro) :Crenolanib has 25-fold more affinity for PDGFRA/B compared with KIT, and is approximately 135-fold more potent than STI571 for inhibiting the PDGFRA D842V mutation. The IC50 for crenolanib for a KIT exon 11 deletion mutant kinase is greater than 1,000 versus 8 nM for STI571. Crenolanib has low nanomolar potency against the V561D + D842V-mutant kinase that is similar to its potency against the isolated D842V mutation. Both STI571 and crenolanib potently inhibit the kinase activity of the fusion oncogene with IC50 values of 1 and 21 nM, respectively, and inhibits PDGFRA activation in this cell line with IC50 values of 93 and 26 nM, respectively. HL60/VCR and K562/ABCB1 cells, overexpressing ABCB1, are 6.9- and 3.6-fold resistant to crenolanib, respectively, in relation to parental HL60 and K562 cells. PSC-833 fully reverses resistance to crenolanib in both HL60/VCR and K562/ABCB1 cells. Crenolanib (1 nM-10 μM) stimulates ABCB1 ATPase activity in a concentration-dependent manner. Crenolanib treatment does not increase the cell surface expression of ABCB1. Crenolanib inhibits [125I]-IAAP photocrosslinking of ABCB1 at high concentrations, with 50 % inhibition at 10 μM, but has little effect at lower concentrations, below 1 μM. Crenolanib decreases NSCLC cell viability, induces apoptosis in NSCLC cells, and inhibits cell migration in NSCLC cells. (In Vivo) :Crenolanib (10 mg/kg and 20 mg/kg) suppresses non-small-cell lung cancer tumor growth in vivo and induces tumor cell apoptosis, and the dosage of crenolanib applied is well tolerated by recipient mice.