IHMT-TRK-284

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IHMT-TRK-284

本产品不向个人销售，仅用作科学研究，不用于任何人体实验及非科研性质的动物实验。

CAS NO:

2416844-79-4

包装与价格：

包装	价格(元)
100mg	电议
250mg	电议
500mg	电议

产品介绍

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。

生物活性

IHMT-TRK-284 (Compound 34) is a potent, orally activetype IITRKkinaseinhibitor withIC₅₀values of 10.5, 0.7, and 2.6 nM toTRKA, B, andCrespectively. 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)

CSF1R

1.2 nM (IC₅₀)

PDGFRα

24.2 nM (IC₅₀)

PDGFRβ

95.7 nM (IC₅₀)

Abl1

83.6 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].

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. GI₅₀for KM-12-LUC cells was 0.002 μM.
Antiproliferative effects of IHMT-TRK-284 against a panel of kinase transformed BaF3 cells^[1].

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

Antiproliferative effects of IHMT-TRK-284 against a panel of TRKs wt/mutants transformed BaF3 cells (n = 3)^[1].
Showed antiproliferative effects with GI₅₀s of 1.4 ± 0.011, 0.007 ± 0.001, 0.003 ± 0.001, 0.004 ± 0.001, 0.194 ± 0.013, 0.034 ± 0.002, 0.002 ± 0.001 μM against BaF3, BaF3-LMNA-TRKA, BaF3-LMNA-TRKA-V573M, BaF3-LMNA-TRKA-F589L, BaF3-LMNA-TRKA-G595R, BaF3-LMNA-TRKA-G667C, BaF3-LMNA-TRKA-G667S cells, respectively.

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) (EC₅₀less 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].

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 dogs^a^[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
T_1/2(h)	2.6	3.4	2.7	2.5	0.03	11.8
Vz (mL/kg)	4934	31567	9682	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.