TAK-632

• CAT Number: I000893
• CAS Number: 1228591-30-7
• Molecular Formula: C₂₇H₁₈F₄N₄O₃S
• Molecular Weight: 554.51
• Purity: ≥95%
• Target: Raf
• Solubility: in DMSO > 10 mM
• Storage: Store at -20°C
• IC50: 2.4 nM (BRAF V600E); 1.4 nM (C-RAF); 160 nM (VEGFR) [1]
• InChI: InChI=1S/C27H18F4N4O3S/c28-19-7-6-17(12-21(19)33-23(36)11-14-2-1-3-16(10-14)27(29,30)31)38-22-InChI=1S/C27H18F4N4O3S/c28-19-7-6-17(12-21(19)33-23(36)11-14-2-1-3-16(10-14)27(29,30)31)38-22-9-8-20-24(18(22)13-32)39-26(34-20)35-25(37)15-4-5-15/h1-3,6-10,12,1
• InChIKey: OJFKUJDRGJSAQB-UHFFFAOYSA-N
• SMILES: O=C(NC1=C(F)C=CC(OC2=CC=C(N=C(NC(C3CC3)=O)S4)C4=C2C#N)=C1)CC5=CC(C(F)(F)F)=CC=C5

TAK-632 is a selective pan-RAF kinase inhibitor with IC50 values of 2.4/1.4 nM for BRAF V600E/c-RAF; > 60 fold selectivity over VEGFR.IC50 Value: 2.4 nM (BRAF V600E); 1.4 nM (C-RAF); 160 nM (VEGFR) [1]Target: B-Raf; C-RafIn vitro: TAK-632 inhibited phosphorylation of MEK (pMEK) in melanoma A375 cells (BRAFV600E) with an IC50 value of 12 nM. Downstream inhibition of ERK phosphorylation (pERK) was also observed in A375 cells with an IC50 value of 16 nM [1]. TAK-632 suppresses RAF activity in BRAF wild-type cells with minimal RAF paradoxical activation. Our analysis using RNAi and TAK-632 in preclinical models reveals that the MAPK pathway of NRAS-mutated melanoma cells is highly dependent on RAF. TAK-632 induces RAF dimerization but inhibits the kinase activity of the RAF dimer, probably because of its slow dissociation from RAF. As a result, TAK-632 demonstrates potent anti-proliferative effects both on NRAS-mutated melanoma cells and BRAF-mutated melanoma cells with acquired resistance to BRAF inhibitors through NRAS mutation or BRAF truncation. Furthermore, we demonstrate that the combination of TAK-632 and the MAPK kinase (MEK) inhibitor TAK-733 exhibits synergistic anti-proliferative effects on these cells [2].In vivo: In vivo efficacy of TAK-632 was evaluated using an SD formulation in a human melanoma A375 (BRAFV600E) xenograft model in F344 nude rats. Reflecting the potent in vitro pMEK inhibition, oral single administration of TAK-632 inhibited pERK in tumors at 8 h after its administration over a dose range of 1.924.1 mg/kg. In particular, 9.724.1 mg/kg dosing with TAK-632 strongly inhibited pERK levels to 11% of the control. We examined the antitumor efficacy of TAK-632 administered twice daily for 14 days in an A375 xenograft model in rats. TAK-632 exhibited dose-dependent antitumor efficacy without severe body weight reduction over a dose range of 3.924.1 mg/kg. Significant tumor regression was observed at 9.7 mg/kg and 24.1 mg/kg (T/C = 2.1% and 12.1%, respectively). TAK-632 was orally administered as an SD formulation and suppressed the growth of HMVII tumors withT/C values of 52%, 26%, and 0% at doses of 3.9 mg/kg, 9.7 mg/kg, and 24.1 mg/kg, respectively [1].

Reference

1:Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma. Nakamura A, Arita T, Tsuchiya S, Donelan J, Chouitar J, Carideo E, Galvin K, Okaniwa M, Ishikawa T, Yoshida S.Cancer Res. 2013 Dec 1;73(23):7043-55. doi: 10.1158/0008-5472.CAN-13-1825. Epub 2013 Oct 11. PMID: 24121489 Free Article2: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. Okaniwa M, Hirose M, Arita T, Yabuki M, Nakamura A, Takagi T, Kawamoto T, Uchiyama N, Sumita A, Tsutsumi S, Tottori T, Inui Y, Sang BC, Yano J, Aertgeerts K, Yoshida S, Ishikawa T.J Med Chem. 2013 Aug 22;56(16):6478-94. doi: 10.1021/jm400778d. Epub 2013 Aug 1. PMID: 23906342