TAK-632 is a potent pan-Raf inhibitor with IC50 of 8.3 nM and 1.4 nM for B-Raf(wt) and C-Raf in cell-free assays, respectively, showing less or no inhibition against other tested kinases.
Storage Temp
Store at -20°C
Shipped In
Ice chest + Ice pads
Grade
Moligand™
Action Type
INHIBITOR
Mechanism of action
Inhibitor of aurora kinase B;Inhibitor of B-Raf proto-oncogene; serine/threonine kinase;Inhibitor of fibroblast growth factor receptor 3;Inhibitor of platelet derived growth factor receptor beta;Inhibitor of Raf-1 proto-oncogene; serine/threonine kinase;I
Product Description
Information
TAK-632 is a potent pan-Rafinhibitor withIC50of 8.3 nM and 1.4 nM for B-Raf(wt) and C-Raf in cell-free assays, respectively, showing less or no inhibition against other tested kinases.
TAK-632 inhibits phosphorylation of MEK and ERK in melanoma A375 cells (BRAFV600E) with IC50 of 12 nM and 16 nM, respectively. In human melanoma HMVII cells (NRASQ61K/BRAFG469V), TAK-632 also shows strong inhibition of pMEK and pERK with IC50 of 49 nM and 50 nM, respectively. Moreover, TAK-632 also exhibits antiproliferative activity in both A375 and HMVII cells with GI50 of 66 nM and 200 nM, respectively. TAK-632 induces RAF dimerization but inhibits the kinase activity of the RAF dimer because of its slow dissociation from RAF. The combination of TAK-632 and TAK-733 exhibits synergistic antiproliferative effects in BRAF- and NRAS-mutated melanoma cells.
In vivo
TAK-632 shows superior oral bioavailability in both rats and dogs. TAK-632 (3.9–24.1 mg/kg, p.o.) exhibits dose-dependent antitumor efficacy without severe body weight reduction in a melanoma A375 (BRAFV600E) xenograft model and a human melanoma HMVII (NRASQ61K/BRAFG469V) xenograft in rats. In NRAS-mutant melanoma SK-MEL-2 xenograft model, TAK-632 (60 or 120 mg/kg, p.o.) also exhibits potent antitumor efficacy without severe toxicity.
1.Okaniwa M, Hirose M, Arita T, Yabuki M, Nakamura A, Takagi T, Kawamoto T, Uchiyama N, Sumita A, Tsutsumi S et al.. (2013) Discovery of a selective kinase inhibitor (TAK-632) targeting pan-RAF inhibition: design, synthesis, and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives.. J Med Chem, 56 (16):(6478-94). [PMID:23906342][10.1021/op500134e]
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H2224297