TAK-632 is a multi-target inhibitor, targeting PDGFRβ, FGFR3, GSK3β, CDK2, P38α, PDGFRα, TIE2, and CDK1 with IC50 values ranging between 120-790 nM. Additionally, it inhibits CHK1, IKKβ, and MEK1 within an IC50 span of 1400-1700 nM. Preincubation for 1 hour allows TAK-632 to inhibit BRAF and CRAF competitively to ATP, with low ATP concentration IC50s at 15 nM for BRAF and 8.1 nM for CRAF. At higher ATP concentrations, the inhibition IC50s for BRAF and CRAF increase to 58 nM and 62 nM, respectively. In HMVII cells, TAK-632 effectively inhibits pMEK and pERK with IC50 values of 49 nM and 50 nM, respectively[1]. In terms of antiproliferative activity, TAK-632 is potent in both A375 and SK-MEL-2 cell lines, exhibiting GI50 values between 40-190 nM in A375 cells and 190-250 nM in SK-MEL-2 cells[2].
体内研究
TAK-632 shows significantly improved solubility (740 μg/mL) in pH 6.8 phosphate buffer and has notable oral absorption in rats (with a 25 mg/kg dose leading to an AUC of 32.47 μg h/mL and a bioavailability of 51.7%). In dogs, a 10 mg/kg oral dose of TAK-632 demonstrates excellent oral bioavailability (108%). Following a single oral administration, TAK-632 suppresses pERK in tumors at 8 hours post-dose across a range of 1.9-24.1 mg/kg, with 9.7-24.1 mg/kg doses significantly reducing pERK levels to 11% of the control. TAK-632 shows a dose-dependent antitumor effect without major body weight loss over a dosage range of 3.9-24.1 mg/kg, achieving significant tumor shrinkage at doses of 9.7 mg/kg and 24.1 mg/kg [1].
When orally administered at 60 mg/kg daily or 120 mg/kg daily for 21 days, TAK-632 shows strong antitumor effectiveness against NRAS-mutant melanoma in a SK-MEL-2 xenograft model, without significant toxicity (T/C=37% and 29%, respectively, both P<0.001)[2].
体外研究
TAK-632 is a multi-target inhibitor, targeting PDGFRβ, FGFR3, GSK3β, CDK2, P38α, PDGFRα, TIE2, and CDK1 with IC50 values ranging between 120-790 nM. Additionally, it inhibits CHK1, IKKβ, and MEK1 within an IC50 span of 1400-1700 nM. Preincubation for 1 hour allows TAK-632 to inhibit BRAF and CRAF competitively to ATP, with low ATP concentration IC50s at 15 nM for BRAF and 8.1 nM for CRAF. At higher ATP concentrations, the inhibition IC50s for BRAF and CRAF increase to 58 nM and 62 nM, respectively. In HMVII cells, TAK-632 effectively inhibits pMEK and pERK with IC50 values of 49 nM and 50 nM, respectively[1].
In terms of antiproliferative activity, TAK-632 is potent in both A375 and SK-MEL-2 cell lines, exhibiting GI50 values between 40-190 nM in A375 cells and 190-250 nM in SK-MEL-2 cells[2].
TAK-632 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HT-29 cells
20 µM
16 hours
TAK-632 protected HT-29 cells from TSZ-induced necroptosis
Br J Pharmacol. 2019 Jun;176(12):2095-2108.
THP1-1 cells
10 µM
24 hours
To screen a small molecule compound library to identify mechanisms modulating TREM2 surface expression.
J Biol Chem. 2021 Jan-Jun;296:100218.
HFF cells
0.6131 µM
72 hours post-infection
Evaluate anti-N. caninum activity of TAK-632 in vitro.
Parasit Vectors. 2024 Mar 8;17(1):118.
TAK-632 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 J mice
TNF-induced systemic inflammatory response syndrome (SIRS) model
Oral
100 mg/kg
Single dose, 2 hr duration
TAK-632 protected mice from TNF-induced SIRS, alleviating hypothermia and death
Br J Pharmacol. 2019 Jun;176(12):2095-2108.
BALB/c mice
Neospora caninum infection model
Intraperitoneal injection
20, 40, and 60 mg/kg
Once daily for 10 consecutive days
Assess the effects of TAK-632 on parasite burden in vivo.
Inhibition of N-terminal GST-tagged MEK1 (unknown origin) expressed in 293 cells using GST-ERK1(K71A) as substrate after 20 mins, IC50=3.7 μM
23906342
human A375 cells
Function assay
2 h
Inhibition of BRAF V600E mutant in human A375 cells assessed as phosphorylation of MEK after 2 hrs by Western blotting analysis, IC50=12 nM
23906342
human HMVII cells
Function assay
2 h
Inhibition of NRASQ61k/BRAFG469V-mutant in human HMVII cells assessed as phosphorylation of MEK after 2 hrs by Western blotting analysis, IC50=49 nM
23906342
human HMVII cells
Proliferation assay
72 h
Antiproliferative activity against human HMVII cells assessed as growth inhibition after 72 hrs by chemi-luminescence cell viability assay, GI50=0.2 μM
23906342
human HT-29 cells
Function assay
Inhibition of BRAF V600E mutant in human HT-29 cells assessed as phosphorylation of MEK, IC50=75 nM
搜索
