IHMT-TRK-284

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上海金畔生物科技有限公司为生命科学和医药研发人员提供生物活性分子抑制剂、激动剂、特异性抑制剂、化合物库、重组蛋白，专注于信号通路和疾病研究领域。

IHMT-TRK-284 

IHMT-TRK-284 (Compound 34) 是一种有效的、具有口服活性的 type II TRK kinase 抑制剂，对 TRKA, B, C 的 IC50 值分别为 10.5, 0.7和2.6 nM。 IHMT-TRK-284 在激酶组中表现出良好的选择性、具有良好的体内抗肿瘤效果。

IHMT-TRK-284

IHMT-TRK-284 Chemical Structure

CAS No. : 2416844-79-4

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生物活性

IHMT-TRK-284 (Compound 34) is a potent, orally active type II TRK kinase inhibitor with IC50 values of 10.5, 0.7, and 2.6 nM to TRKA, B, and C respectively. IHMT-TRK-284 displays great selectivity profile in the kinome and good in vivo antitumor efficacies[1].

IC50 & Target

TrkB

0.7 nM (IC50)

TrkC

2.6 nM (IC50)

TrkA

10.5 nM (IC50)

PDGFRα

24.2 nM (IC50)

PDGFRβ

95.7 nM (IC50)

Abl1

83.6 nM (IC50)

CSF1R

1.2 nM (IC50)

KIT

2167 nM (IC50)

体外研究
(In Vitro)

IHMT-TRK-284 (Compound 34) (0-10 µM, 72 h) shows antiproliferative effects against BaF3 cells, a panel of kinase transformed BaF3 cells, and KM-12-LUC cells[1].
IHMT-TRK-284 (0-10 µM, 24 h) induces apoptosis and arrests the cell cycle into G0/G1 phase in KM-12-LUC cells[1].
IHMT-TRK-284 exerts its inhibitory effect to the colon cancer cells through on-target inhibition of TRK[1].
IHMT-TRK-284 could overcome drug resistant mutants including V573M and F589L in the ATP binding pocket as well as G667C/S in the DFG region[1].
IHMT-TRK-284 shows selectivity over VEGFR2 kinase[1].

Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Proliferation Assay[1]

Cell Line: BaF3 cells, a panel of kinase transformed BaF3 cells, and KM-12-LUC cells
Concentration: 0-10 µM
Incubation Time: 72 h
Result: Showed antiproliferative effects against BaF3 cells, a panel of kinase transformed BaF3 cells, and KM-12-LUC cells. GI50 for KM-12-LUC cells was 0.002 µM.
Antiproliferative effects of IHMT-TRK-284 against a panel of kinase transformed BaF3 cells[1].

Target GI50 (nM)
BaF3-TEL-ABL 411.1
BaF3-TEL-CSF1R 4
BaF3-TEL-KIT 923.2
BaF3-TEL-PDGFRα 1.7
BaF3-TEL-PDGFRβ 1.4
BaF3-TEL-TRKA 8.5
BaF3-TEL-TRKB 8.2
BaF3-TEL-TRKC 27.3
BaF3-TEL-VEGFR2 1180


Antiproliferative effects of IHMT-TRK-284 against a panel of TRKs wt/mutants transformed BaF3 cells (n = 3)[1].

Cells GI50 (µM)
BaF3 1.4 ± 0.011
BaF3-LMNA-TRKA 0.007 ± 0.001
BaF3-LMNA-TRKA-V573M 0.003 ± 0.001
BaF3-LMN

Western Blot Analysis[1]

Cell Line: BaF3-TEL-TRKA, BaF3-TEL-TRKB, BaF3-TEL-TRKC, BaF3-LMNATRKA-V573M, BaF3-LMNA-TRKA-F589L, BaF3-LMNA-TRKA-G595R, BaF3-LMNA-TRKA-G667C/S, and KM-12-LUC cells
Concentration: 0, 0.01, 0,03, 0.1, 0.3, 1, 3, and 10 µM
Incubation Time: 2 h
Result: In transformed BaF3 cells: Inhibited the phosphorylation of TRKA Y490 (EC50 = 0.026 µM) and corresponding tyrosine residues TRKB Y515 (EC50 = 0.069 µM) and TRKC Y516 (EC50 = 0.029 µM); potently inhibited the phosphorylation of Y490 in V573M, F589L, and G667C/S mutants with EC50s of 0.013 µM, 0.021 µM, 0.067 µM, and 0.074 µM respectively. In KM-12-LUC cells: Blocked the phosphorylation of TRKA Y490 at the concentration of 0.01 µM; remarkably inhibited the phosphorylation of downstream signaling mediators AKT T308/S473 and ERK1/2 (T202/Y204) (EC50 less than 0.03 µM).

Apoptosis Analysis[1]

Cell Line: KM-12-LUC cells
Concentration: 0, 0.01, 0,03, 0.1, 0.3, 1, 3, and 10 µM
Incubation Time: 24 h
Result: Induced dose-dependent cell apoptotic death.

Cell Cycle Analysis[1]

Cell Line: KM-12-LUC cells
Concentration: 0, 0.01, 0,03, 0.1, 0.3, 1, 3, and 10 µM
Incubation Time: 24 h
Result: Arrested the cell cycle into G0/G1 phase.

体内研究
(In Vivo)

IHMT-TRK-284 (Compound 34) (40 and 80 mg/kg; p.o.; daily, 10 days) shows good in vivo PK and antitumor efficacy properties[1].

Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: Four-week old female nu/nu mice, one million BaF3-TELTRKA, BaF3-TEL-TRKB, BaF3-TEL-TRKC, BaF3-LMNA-TRKA-F589L, BaF3-LMNA-TRKA-G667S, and five million KM-12-LUC cells in DMEM medium were formulated as a 1:1 mixture with matrigel and injected into the subcutaneous space on the right flank of nu/nu mice[1]
Dosage: 40 mg/kg and 80 mg/kg
Administration: Daily oral gavage, 10 days
Result: Dose-dependently inhibited the BaF3-TEL-TRKA, BaF3-TEL-TRKB, and BaF3-TEL-TRKC tumor progression with TGI (tumor growth inhibition) of 68%, 93%, and 58%. Dose-dependently inhibited the tumor progression and exhibited the TGI of 93% at 40 mg/kg/day and 95% at 80 mg/kg/day in KM-12-LUC cells inoculated xenograft mouse model. Potently inhibited the tumor growth with TGI values of 88% and 89% respectively at 80 mg/kg dosage in BaF3- LMNA-TRKA-F589L and BaF3-LMNA-TRKA-G667S cells.
Animal Model: Mice, sprague dawley rats, and beagle dogs[1]
Dosage: 1 mg/kg and 10 mg/kg
Administration: Intravenous injection and oral administration (Pharmacokinetic Analysis)
Result: Pharmacokinetic study of IHMT-TRK-284 in mice, sprague dawley rats, and beagle dogsa[1]

Parameter Mice
i.v. (1 mg/kg)		 Mice
p.o. (10 mg/kg)		 Rats
i.v. (1 mg/kg)		 Rats
p.o. (10 mg/kg)		 Beagle Dogs
i.v. (1 mg/kg)		 Beagle Dogs
p.o. (10 mg/kg)
AUC(0-t)
(ng/mL*h)		 748 1431 393 952 323 464
Tmax (h) 0.033 1.5 0.03 4.7 0.08 4.3
T1/2 (h) 2.6 3.4 2.7 2.5 0.03 11.8
Vz (mL/kg) 4934 31567 9682

分子量

473.59

Formula

C25H27N7OS
CAS 号

2416844-79-4
运输条件

Room temperature in continental US; may vary elsewhere.
储存方式

Please store the product under the recommended conditions in the Certificate of Analysis.
参考文献

  • [1]. Beilei Wang, et al. Discovery of (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (IHMT-TRK-284) as a novel orally available type II TRK kinase inhibitor capable of overcoming multiple resistant mutants. Eur J Med Chem. 2020 Dec 1;207:112744.

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