TAK-632

TAK-632 is a selective inhibitor of BRAF, CRAF and BRAF-V600E kinase with IC50 value of 8.3 nM, 1.4 nM and 2.4 nM [1].

RAF kinases are a family of three serine/threonine-specific protein kinases and play an important role in the RAS-RAF-MEK-ERK signal transduction cascade, as well as the mitogen-activated protein kinase (MAPK) cascade [2].

TAK-632 is a potent pan-RAF kinase inhibitor and has a higher selectivity compared with the reported pan-RAF kinase inhibitor vemurafenib. When tested with SK-MEL-2 cells, TAK-632 showed induction on the BRAF-CRAF dimmers formation in a dose-dependent manner. In melanoma cell lines A375 and SK-MEL-2, TAK-632 exhibited significant antiproliferative effects with GI50 value of 6 nom/L and 11 nom/L, respectively [1].

In mouse model with SK-MEL-2 subcutaneous xenograft, oral administration of TAK-632 caused significant reduction of phosphorylated ERK and tumor growth at the dose of 60 or 120 mg/kg/d once daily for 21 days without severe toxicity [1].

It is also reported that TAK-632 is a potent inhibitor of pERK with IC50 value of 25 nM [1].

References:
[1].  Nakamura, A., et al., Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma. Cancer Res, 2013. 73(23): p. 7043-55.
[2].  Korkut, A., et al., Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife, 2015. 4.

Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma.[Pubmed:24121489]

Cancer Res. 2013 Dec 1;73(23):7043-55.

The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of melanoma cells. Somatic mutations in BRAF and NRAS are frequently observed in melanoma. Recently, the BRAF inhibitors vemurafenib and dabrafenib have emerged as promising agents for the treatment of melanoma patients with BRAF-activating mutations. However, as BRAF inhibitors induce RAF paradoxical activation via RAF dimerization in BRAF wild-type cells, rapid emergence of acquired resistance and secondary skin tumors as well as presence of few effective treatment options for melanoma bearing wild-type BRAF (including NRAS-mutant melanoma) are clinical concerns. Here, we demonstrate that the selective pan-RAF inhibitor 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. We also show that 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 antiproliferative 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 antiproliferative effects on these cells. Our findings characterize the unique features of TAK-632 as a pan-RAF inhibitor and provide rationale for its further investigation in NRAS-mutated melanoma and a subset of BRAF-mutated melanomas refractory to BRAF inhibitors.

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.[Pubmed:23906342]

J Med Chem. 2013 Aug 22;56(16):6478-94.

With the aim of discovering a selective kinase inhibitor targeting pan-RAF kinase inhibition, we designed novel 1,3-benzothiazole derivatives based on our thiazolo[5,4-b]pyridine class RAF/VEGFR2 inhibitor 1 and developed a regioselective cyclization methodology for the C-7-substituted 1,3-benzothiazole scaffold utilizing meta-substituted anilines. Eventually, we selected 7-cyano derivative 8B (TAK-632) as a development candidate and confirmed its binding mode by cocrystal structure with BRAF. Accommodation of the 7-cyano group into the BRAF-selectivity pocket and the 3-(trifluoromethyl)phenyl acetamide moiety into the hydrophobic back pocket of BRAF in the DFG-out conformation contributed to enhanced RAF potency and selectivity vs VEGFR2. Reflecting its potent pan-RAF inhibition and slow off-rate profile, 8B demonstrated significant cellular activity against mutated BRAF or mutated NRAS cancer cell lines. Furthermore, in both A375 (BRAF(V600E)) and HMVII (NRAS(Q61K)) xenograft models in rats, 8B demonstrated regressive antitumor efficacy by twice daily, 14-day repetitive administration without significant body weight loss.