CAS No. : 1001917-37-8

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For research use only. Not Intended for Therapeutic Use!
Cat No:I000076
Molecular Formula:C25H21N5O3S
Molecular Weight:471.53
IC50:1 nM (Wt c-Met); 2.0 nM (c-Met N1100Y) [1]
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Appearance:Solid powder
Purity: > 98%
Cat No:I000076
Cas No:1001917-37-8

MK8033 is a novel and specific dual ATP competitive c-Met/Ron inhibitor (IC50=1 nM Wt c-Met) under investigation as a treatment for cancer.
IC50 Value: 1 nM (Wt c-Met); 2.0 nM (c-Met N1100Y) [1]
Target: c-Met/Ron
in vitro: MK-8033 binds 3-fold more tightly to phosphorylated c-Met kinase domain (Kd= 3.2 nM) than to its unphosphorylated counterpart (Kd = 10.4 nM). Signigicantly, MK-8033 potently inhibits kinase activity of three oncogenic c-Met activation loop mutants, Y1230C, Y1230H, and Y1235D (IC50s ranging from 0.6 to 1 nM at 50 uM ATP) in addition to other c-Met activating mutants N1100Y and M1250T. MK-8033 potently inhibited GTL-16 proliferation with an IC50 of 582 ± 30 nM. By contrast the HCT116 cell line, which does not harbor basal c-Met activation, was not inhibited by MK-8033 (IC50 > 10000 nM) [1]. MK-8033 radiosensitized the high-c-Met-expressing EBC-1 and H1993 cells but not the low-c-Met-expressing cell lines A549 and H460. However, irradiation of A549 and H460 cells increased the expression of c-Met protein at 30 minutes after the irradiation. Subsequent targeting of this up-regulated c-Met by using MK-8033 followed by a second radiation dose reduced the clonogenic survival of both A549 and H460 cells. MK-8033reduced the levels of radiation-induced phosphorylated (activated) c-Met in A549 cells [2].
in vivo: MK-8033 was orally dosed in GTL-16 tumor xenograft bearing mice. Mice were euthanized 1 h after dosing and tested for p-Met (Y1349) in tumors and MK-8033 concentrations in plasma. At 100 mg/kg,essentially complete inhibition of p-Met (Y1349) was achieved. An in vivo IC50 of 1.3 uM was deduced from the relationship between plasma MK-8033 level and Met pY1349. Treatment with escalating dosed of MK-8033 for 21 days lead to antitumor efficacies in a dose-dependent manner. Dosing at 3, 10, 30, and 100 mg/kg resulted in 22, 18, 57, and 86% tumor growth inhibition, respectively, relative to tumor from vehicle-treated mice.

1:J Med Chem. 2013 Mar 28;56(6):2294-310. doi: 10.1021/jm301619u. Epub 2013 Mar 18. Discovery of 1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide (MK-8033): A Specific c-Met/Ron dual kinase inhibitor with preferential affinity for the activated state of c-Met.Northrup AB,Katcher MH,Altman MD,Chenard M,Daniels MH,Deshmukh SV,Falcone D,Guerin DJ,Hatch H,Li C,Lu W,Lutterbach B,Allison TJ,Patel SB,Reilly JF,Reutershan M,Rickert KW,Rosenstein C,Soisson SM,Szewczak AA,Walker D,Wilson K,Young JR,Pan BS,Dinsmore CJ, PMID: 23379595 DOI: 10.1021/jm301619u
Abstract: This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase conformation.
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