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Datasheet of TAK-632

Description:.
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.
In 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.
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.
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 1.9?24.1 mg/kg. In particular, 9.7?24.1 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 3.9?24.1 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..

Chemical Information
Catalog

DC7307

Purity of current batch:

>98%

Molecular Weight (MW)

554.52

Molecular Formula

C27H18F4N4O3S

CAS No.

1228591-30-7

Solubility (25C)

DMSO

Storage

Store at -20C (desiccating conditions).

Handling:
Providing storage is as stated on the product vial and the vial is kept tightly sealed, the product can be stored for up to 24 months.
Wherever possible, you should prepare and use solutions on the same day. However, if you need to make up stock solutions in
advance, we recommend that you store the solution as aliquots in tightly sealed vials at -20C. Generally, these will be useable
for up to one month. Before use, and prior to opening the vial we recommend that you allow your product to equilibrate to room
temperature for at least 1 hour.