Biological Activity
TAK-632 is a potent pan-RAF inhibitor with IC50 of 1.4, 2.4 and 8.3 nM for CRAF, BRAFV600E, BRAFWT, respectively.
In Vitro
TAK-632 inhibits PDGFRβ, FGFR3, GSK3β, CDK2, P38α, PDGFRα, TIE2, and CDK1 with a range of IC50 values from 120-790 nM. CHK1, IKKβ, and MEK1 are inhibited over an IC50 range of 1400-1700 nM. With 1 h of preincubation time, TAK-632 inhibits BRAF and CRAF in an ATP competitive manner (at low ATP concentrations BRAF IC50: 15 nM; CRAF: 8.1 nM). The respective biochemical activity of TAK-632 against BRAF and CRAF reduces to IC50 values of 58 nM and 62 nM at high ATP concentrations.TAK-632 demonstrates strong inhibition of pMEK and pERK in HMVII cells with IC50 values of 49 nM and 50 nM, respectively[1]. TAK-632 shows strong antiproliferative effects both in A375 and SK-MEL-2 cells (GI50 of 40-190 nM in A375 cells and GI50 of 190-250 nM in SK-MEL-2 cells)[2].
In Vivo
TAK-632 demonstrates dramatically improved solubility (740 μg/mL) in pH 6.8 phosphate buffer and exhibits significant oral absorption (at a dose of 25 mg/kg, AUC, 32.47 μg h/mL; F, 51.7%) in rats. In a dog PK study, 10 mg/kg administration of TAK-632 also shows superior oral bioavailability (F: 108%).Oral single administration of TAK-632 inhibits pERK in tumors at 8 h after its administration over a dose range of 1.9-24.1 mg/kg. In particular, 9.7-24.1 mg/kg dosing with TAK-632 strongly inhibits pERK levels to 11% of the control. TAK-632 exhibits dose-dependent antitumor efficacy without severe body weight reduction over a dose range of 3.9-24.1 mg/kg. Significant tumor regression is observed at 9.7 mg/kg and 24.1 mg/kg (T/C=−2.1% and −12.1%, respectively)[1]. TAK-632 exhibits potent antitumor efficacy when orally administered at 60 mg/kg once daily (T/C=37%, P<0.001) or at 120 mg/kg once daily (T/C=29%, P<0.001) for 21 days without severe toxicity in NRAS-mutant melanoma using a SK-MEL-2 xenograft model[2].
References & source
Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.
