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 |
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| 分子量 |
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| Formula |
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| CAS 号 |
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| 运输条件 |
Room temperature in continental US; may vary elsewhere.
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| 储存方式 |
Please store the product under the recommended conditions in the Certificate of Analysis.
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| 参考文献 |
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[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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