TAK-632

1228591-30-7

C27H18F4N4O3S

DMSO : 100 mg/mL (180.34 mM; Need ultrasonic)

MAPK/ERK Pathway; Cell Cycle/DNA Damage; Epigenetics

TAK-632 is a potent pan-RAF inhibitor with IC₅₀ of 1.4, 2.4 and 8.3 nM for CRAF, BRAF^V600E, BRAF^WT, respectively. IC50 & Target: IC50: 1.4 nM (C-RAF), 2.4 nM (BRAF^V600E), 8.3 nM (BRAF^WT), 66 nM (Aurora B), 160 nM (VEGFR)^[1] In Vitro: TAK-632 inhibits PDGFRbeta, FGFR3, GSK3beta, CDK2, P38alpha, PDGFRalpha, TIE2, and CDK1 with a range of IC₅₀ values from 120-790 nM. CHK1, IKKbeta, 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 ug/mL) in pH 6.8 phosphate buffer and exhibits significant oral absorption (at a dose of 25 mg/kg, AUC, 32.47 ug 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].