Altiratinib

1345847-93-9

C26H21F3N4O4

DMSO : >= 33 mg/mL (64.65 mM)

Protein Tyrosine Kinase/RTK; Protein Tyrosine Kinase/RTK; Protein Tyrosine Kinase/RTK; Protein Tyrosine Kinase/RTK; Neuronal Signaling

Altiratinib (DCC-2701) is a multi-targeted kinase inhibitor with IC₅₀s of 2.7, 8, 9.2, 9.3, 0.85, 4.6, 0.83 nM for MET, TIE2, VEGFR2, FLT3, Trk1, Trk2, and Trk3 respectively. IC50 & Target: IC50: 2.7 nM (MET), 8 nM (TIE2), 9.2 nM (VEGFR2), 9.3 nM (FLT3), 0.85 nM (Trk1), 4.6 nM (Trk2), 0.93 nM (Trk3)^[1] In Vitro: Altiratinib also inhibits MET isoforms MET^D1228H, MET ^D1228N, MET^Y1230C, MET^Y1230D, MET^Y1230H, MET^M1250T with IC₅₀s of 3.6, 1.3, 1.2, 0.37, 1.5 and 6 nM, respectively. Altiratinib inhibits MET phosphorylation with IC₅₀ values of 0.85 and 2.2 nM, respectively. In the U-87 glioblastoma cell line, MET and HGF are both expressed. Altiratinib blocks autocrine activation of MET phosphorylation in these cells (IC₅₀=6.2 nM). Altiratinib potently inhibits cellular proliferation in MET-amplified EBC-1 and MKN-45 cells, as well as TPM3-TRKA fusion KM-12 cells. Activation of MET is known to increase the motility and invasiveness of cancer cells: Altiratinib inhibits HGF-induced A549 cell migration, with an IC₅₀ of 13 nM. Altiratinib also inhibits FLT3-ITD mutant MV-4-11 cell proliferation with an IC₅₀ of 12 nM^[1]. In Vivo: A single oral dose of 30 mg/kg Altiratinib leads to >95% inhibition of MET phosphorylation for the entire 24-hour period. A single 10 mg/kg oral dose of Altiratinib exhibits complete inhibition of MET phosphorylation through 12 hours and 73% inhibition at 24 hours postdose. Altiratinib dosed at 10 mg/kg twice a day leads to a significant 90% decrease in BLI signal. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood–brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases^[1].