IHMT-TRK-284
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.
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- No. CAS: 2416844-79-4
- Fòrmula: C25H27N7OS
- Peso molecular:473.59
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Actividad biológica
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Actividad biológica
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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) |
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Cell Line
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Type | Value | Description | References |
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| BaF3 | GI50 |
1.4 μM
Compound: 34
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Antiproliferative activity in mouse BAF3 cells assessed as growth inhibition after 72 hrs by CCK8 assay
Antiproliferative activity in mouse BAF3 cells assessed as growth inhibition after 72 hrs by CCK8 assay
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[PMID: 32949955] |
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].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:BaF3 cells, a panel of kinase transformed BaF3 cells, and KM-12-LUC cells
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Concentration:0-10 µM
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Incubation Time:72 h
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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 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.
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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
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Concentration:0, 0.01, 0,03, 0.1, 0.3, 1, 3, and 10 µM
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Incubation Time:2 h
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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).
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Cell Line:KM-12-LUC cells
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Concentration:0, 0.01, 0,03, 0.1, 0.3, 1, 3, and 10 µM
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Incubation Time:24 h
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Result:Induced dose-dependent cell apoptotic death.
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Cell Line:KM-12-LUC cells
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Concentration:0, 0.01, 0,03, 0.1, 0.3, 1, 3, and 10 µM
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Incubation Time:24 h
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Result:Arrested the cell cycle into G0/G1 phase.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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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]
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Dosage:40 mg/kg and 80 mg/kg
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Administration:Daily oral gavage, 10 days
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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.
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Animal Model:Mice, sprague dawley rats, and beagle dogs[1]
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Dosage:1 mg/kg and 10 mg/kg
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Administration:Intravenous injection and oral administration (Pharmacokinetic Analysis)
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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 --> 
Chemical Information
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No. CAS 2416844-79-4
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Peso molecular 473.59
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Fòrmula C25H27N7OS
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SMILES
O=C(NC1=NC(C)=C(C2=CC3=C(C=C2)C(/C=C/C4=NC=CC=C4)=NN3)S1)CN5CCN(C)CC5
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Select Batch:Pureza: 99.98%Assay: 99.98%ee.: 99.98%
Referencias
Calculators
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IHMT-TRK-284 Related Classifications
HY-146697 Related Classifications
Keywords
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