Synonym
TAK632, TAK 632, TAK-632
IUPAC/Chemical Name
N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide
InChi Key
OJFKUJDRGJSAQB-UHFFFAOYSA-N
InChi Code
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/h1-3,6-10,12,15H,4-5,11H2,(H,33,36)(H,34,35,37)
SMILES Code
O=C(C1CC1)NC(S2)=NC3=C2C(C#N)=C(OC4=CC(NC(CC5=CC=CC(C(F)(F)F)=C5)=O)=C(F)C=C4)C=C3
Appearance
White solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
TAK-632 is a potent pan-RAF inhibitor with IC50 of 1.4, 2.4 and 8.3 nM for CRAF, BRAFV600E, BRAFWT, respectively.
In vitro activity:
The selective pan-RAF inhibitor TAK-632 suppresses RAF activity in BRAF wild-type cells with minimal RAF paradoxical activation. 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 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, the combination of TAK-632 and the MAPK kinase (MEK) inhibitor TAK-733 exhibits synergistic antiproliferative effects on these cells. The unique features of TAK-632 as a pan-RAF inhibitor provide rationale for its further investigation in NRAS-mutated melanoma and a subset of BRAF-mutated melanomas refractory to BRAF inhibitors.
Reference: Cancer Res. 2013 Dec 1;73(23):7043-55. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=24121489
In vivo activity:
In vivo efficacy of TAK-632 (8B) 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 8B inhibited pERK in tumors at 8 h after its administration over a dose range of 1.9–24.1 mg/kg (Figure 7). In particular, 9.7–24.1 mg/kg dosing with 8B strongly inhibited pERK levels to 11% of the control. The antitumor efficacy of 8B was examined by administration twice daily for 14 days in an A375 xenograft model in rats (Figure 8). Compound 8B 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). Next, antitumor effects of 8B in a human melanoma HMVII (NRASQ61K/BRAFG469V) xenograft model were evaluated in rats (Figure 9). In this study, 8B was orally administered as an SD formulation and suppressed the growth of HMVII tumors with T/C values of 52%, 26%, and 0% at doses of 3.9 mg/kg, 9.7 mg/kg, and 24.1 mg/kg, respectively. This antitumor efficacy was dose-dependent and significant (p < 0.025) compared with that of the vehicle control at all three doses. In this model, the HMVII tumor induced cancer cachexia and resulted in approximately 6% body weight loss in the vehicle control group over the 14-day administration period (body weight change: −8.6 g for the vehicle and +16.5 g for nontumor bearing). Interestingly, dose-dependent recovery of body weight loss was observed. In particular, the group at 24.1 mg/kg showed no signs of body weight loss (body weight change: +28.4 g).
Reference: J Med Chem. 2013 Aug 22;56(16):6478-94. https://doi.org/10.1021/jm400778d
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
30.0 |
54.10 |
| Ethanol |
2.0 |
3.60 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
554.51
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
In vitro protocol:
1. 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. 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. 2013 Aug 22;56(16):6478-94. doi: 10.1021/jm400778d. Epub 2013 Aug 1. PMID: 23906342.
2. Nakamura A, Arita T, Tsuchiya S, Donelan J, Chouitar J, Carideo E, Galvin K, Okaniwa M, Ishikawa T, Yoshida S. Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma. Cancer Res. 2013 Dec 1;73(23):7043-55. doi: 10.1158/0008-5472.CAN-13-1825. Epub 2013 Oct 11. PMID: 24121489.
In vivo protocol:
1. 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. 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. 2013 Aug 22;56(16):6478-94. doi: 10.1021/jm400778d. Epub 2013 Aug 1. PMID: 23906342.
1: Nakamura A, Arita T, Tsuchiya S, Donelan J, Chouitar J, Carideo E, Galvin K, Okaniwa M, Ishikawa T, Yoshida S. Antitumor Activity of the Selective Pan-RAF Inhibitor TAK-632 in BRAF Inhibitor-Resistant Melanoma. Cancer Res. 2013 Dec 1;73(23):7043-55. doi: 10.1158/0008-5472.CAN-13-1825. Epub 2013 Oct 11. PubMed PMID: 24121489.
2: 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. 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. 2013 Aug 22;56(16):6478-94. doi: 10.1021/jm400778d. Epub 2013 Aug 1. PubMed PMID: 23906342.
3: Sung SH, Jeon SW, Son HS, Kim SK, Jung MK, Cho CM, Tak WY, Kweon YO. Factors predictive of risk for complications in patients with oesophageal foreign bodies. Dig Liver Dis. 2011 Aug;43(8):632-5. doi: 10.1016/j.dld.2011.02.018. Epub 2011 Apr 3. PubMed PMID: 21466978.
4: Biró E, Nieuwland R, Tak PP, Pronk LM, Schaap MC, Sturk A, Hack CE. Activated complement components and complement activator molecules on the surface of cell-derived microparticles in patients with rheumatoid arthritis and healthy individuals. Ann Rheum Dis. 2007 Aug;66(8):1085-92. Epub 2007 Jan 29. PubMed PMID: 17261534; PubMed Central PMCID: PMC1954699.
