TAK-632
Modify Date: 2024-01-03 01:04:18
TAK-632 structure
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Common Name | TAK-632 | ||
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| CAS Number | 1228591-30-7 | Molecular Weight | 554.515 | |
| Density | 1.5±0.1 g/cm3 | Boiling Point | N/A | |
| Molecular Formula | C27H18F4N4O3S | Melting Point | N/A | |
| MSDS | N/A | Flash Point | N/A | |
Use of TAK-632TAK-632 is a potent pan-RAF inhibitor with IC50 of 1.4, 2.4 and 8.3 nM for CRAF, BRAFV600E, BRAFWT, respectively. |
| Name | N-[7-cyano-6-[4-fluoro-3-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide |
|---|---|
| Synonym | More Synonyms |
| Description | TAK-632 is a potent pan-RAF inhibitor with IC50 of 1.4, 2.4 and 8.3 nM for CRAF, BRAFV600E, BRAFWT, respectively. |
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| Related Catalog | |
| Target |
c-Raf:1.4 nM (IC50) Braf:8.3 nM (IC50) Aurora B:66 nM (IC50) PDGFRβ:120 nM (IC50) PDGFRα:610 nM (IC50) FGFR3:280 nM (IC50) TIE2:740 nM (IC50) IKKβ:3700 nM (IC50) CDK1:790 nM (IC50) CDK2:580 nM (IC50) p38α:600 nM (IC50) GSK3β:500 nM (IC50) MEK1:3700 nM (IC50) |
| In Vitro | TAK-632 inhibits PDGFRβ, FGFR3, GSK3β, CDK2, P38α, PDGFRα, TIE2, and CDK1 with a range of IC50 values from 120-790 nM. CHK1, IKKβ, and MEK1 are inhibited over an IC50 range of 1400-1700 nM. With 1 h of preincubation time, TAK-632 inhibits BRAF and CRAF in an ATP competitive manner (at low ATP concentrations BRAF IC50: 15 nM; CRAF: 8.1 nM). The respective biochemical activity of TAK-632 against BRAF and CRAF reduces to IC50 values of 58 nM and 62 nM at high ATP concentrations.TAK-632 demonstrates strong inhibition of pMEK and pERK in HMVII cells with IC50 values of 49 nM and 50 nM, respectively[1]. TAK-632 shows strong antiproliferative effects both in A375 and SK-MEL-2 cells (GI50 of 40-190 nM in A375 cells and GI50 of 190-250 nM in SK-MEL-2 cells)[2]. |
| In Vivo | TAK-632 demonstrates dramatically improved solubility (740 μg/mL) in pH 6.8 phosphate buffer and exhibits significant oral absorption (at a dose of 25 mg/kg, AUC, 32.47 μg h/mL; F, 51.7%) in rats. In a dog PK study, 10 mg/kg administration of TAK-632 also shows superior oral bioavailability (F: 108%).Oral single administration of TAK-632 inhibits 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 inhibits pERK levels to 11% of the control. TAK-632 exhibits dose-dependent antitumor efficacy without severe body weight reduction over a dose range of 3.9-24.1 mg/kg. Significant tumor regression is observed at 9.7 mg/kg and 24.1 mg/kg (T/C=−2.1% and −12.1%, respectively)[1]. TAK-632 exhibits potent antitumor efficacy when orally administered at 60 mg/kg once daily (T/C=37%, P<0.001) or at 120 mg/kg once daily (T/C=29%, P<0.001) for 21 days without severe toxicity in NRAS-mutant melanoma using a SK-MEL-2 xenograft model[2]. |
| Kinase Assay | Immunoprecipitated BRAF or CRAF is incubated with recombinant inactive MEK (K97R) at 30°C for 30 minutes in kinase reaction buffer containing ATP/Mg2+. RAS/RAF wild-type (A431, CsFb, and HeLa), KRAS-mutant (A549, HCT-116, and MIA PaCa-2), and NRAS-mutant melanoma (GAK, HMV-II, and SK-MEL-2) cells are treated with TAK-632 (0, 0.32, 1.6, 8, 40, 200, 1000 and 5000 nM) at the indicated concentrations for 2 hours. Cell lysates are analyzed by Western blot analysis[2]. |
| Cell Assay | Cell viability is assessed (3 replicates) using the Sulforhodamine B assay or by the CellTiter-Glo luminescent cell viability assay. The concentrations of TAK-632 that produced 50% growth inhibition (GI50) are calculated using PCP software. The combination index (CI) is calculated using CalcuSyn software. To investigate the antiproliferative activity of TAK-632, we performed proliferation assays in various cell lines harboring mutated BRAF, NRAS, or KRAS. HMV-II, SK-MEL-2, or A375 cells are cotreated with TAK-632 and TAK-733 at the indicated concentrations for 72 hours. Cell viability is measured. The CI value at EC50 is calculated. A375 cells stably expressing NRASQ61K or ΔN-BRAF are cotreated with TAK-632 and TAK-733 at the indicated concentrations for 72 hours. Cell viability is measured. The CI value at EC50 is calculated[2]. |
| Animal Admin | Mice[2] The xenograft-implanted nude mice are used. Mice bearing SK-MEL-2 xenografts are treated once daily for 21 consecutive days with vehicle or TAK-632 at the indicated concentrations (10 mice per each treatment group). Day 0 indicates the beginning of treatment. Tumors are measured twice a week. Mice bearing SK-MEL-2 xenografts are treated once daily (QD) for 3 days with vehicle, TAK-632 at 60 mg/kg (60 mpk), or TAK-632 at 120 mg/kg (120 mpk). Tumor xenografts are obtained at indicated time points after the final treatment and analyzed by Western blot analysis. Individual blots with dividing lines are combined from a single electrophoresis gel. Bars represent densitometric analysis of phospho-ERK, normalized to vehicle-treated control (mean±SD). |
| References |
| Density | 1.5±0.1 g/cm3 |
|---|---|
| Molecular Formula | C27H18F4N4O3S |
| Molecular Weight | 554.515 |
| Exact Mass | 554.103577 |
| PSA | 139.33000 |
| LogP | 5.30 |
| Appearance of Characters | light yellow solid |
| Index of Refraction | 1.660 |
| Storage condition | -20℃ |
| N-{7-Cyano-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide |
| Benzeneacetamide, N-[5-[[7-cyano-2-[(cyclopropylcarbonyl)amino]-6-benzothiazolyl]oxy]-2-fluorophenyl]-3-(trifluoromethyl)- |
| 1SU |
| TAK-632 |
| N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide |
| S7291 |
| TAK632 |