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MedKoo CAT#: 525682
Description: MK-2461 is a novel ATP-competitive multitargeted inhibitor of activated c-Met. MK-2461 inhibited in vitro phosphorylation of a peptide substrate recognized by wild-type or oncogenic c-Met kinases (N1100Y, Y1230C, Y1230H, Y1235D, and M1250T) with IC50 values of 0.4 to 2.5 nmol/L. In tumor cells, MK-2461 effectively suppressed constitutive or ligand-induced phosphorylation of the juxtamembrane domain and COOH-terminal docking site of c-Met, and its downstream signaling to the phosphoinositide 3-kinaseÂ–AKT and RasÂ–extracellular signal-regulated kinase pathways, without inhibiting autophosphorylation of the c-Met activation loop. In cell culture, MK-2461 inhibited hepatocyte growth factor/c-MetÂ–dependent mitogenesis, migration, cell scatter, and tubulogenesis. In a murine xenograft model of c-MetÂ–dependent gastric cancer, a well-tolerated oral regimen of MK-2461 administered at 100 mg/kg twice daily effectively suppressed c-Met signaling and tumor growth. (Cancer Res; 2010, 70(4):1524Â–33)
MedKoo Cat#: 525682
Chemical Formula: C24H25N5O5S
Exact Mass: 495.15764
Molecular Weight: 495.554
Elemental Analysis: C, 58.17; H, 5.09; N, 14.13; O, 16.14; S, 6.47
Synonym: MK2461; MK 2461; MK-2461
IUPAC/Chemical Name: N-((2R)-1,4-Dioxan-2-ylmethyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide
InChi Key: JGEBLDKNWBUGRZ-HXUWFJFHSA-N
InChi Code: InChI=1S/C24H25N5O5S/c1-28-13-18(12-26-28)17-9-22-23(25-11-17)6-4-16-3-5-19(10-21(16)24(22)30)27-35(31,32)29(2)14-20-15-33-7-8-34-20/h3-6,9-13,20,27H,7-8,14-15H2,1-2H3/t20-/m1/s1
SMILES Code: O=S(NC1=CC=C2C(C(C3=CC(C4=CN(C)N=C4)=CN=C3C=C2)=O)=C1)(N(C[C@H]5OCCOC5)C)=O
Phase I study of MK-2461: Fourteen patients (10 M/ 4 F), mean age 54 (range 19-76), have received 31 cycles (range 1-6). Dose levels tested include 60mg daily, 60mg BID, 120mg BID, and 180 mg BID. Toxicity data are available for 11 patients treated at the 60mg daily-120mg BID dosing cohorts. Ten patients (91%) have not experienced > Grade 1 drug-related toxicity. Dose limiting toxicity has not been reached and no objective antitumor responses have been observed. One patient with mucinous carcinoma of the appendix had stable disease for 6 cycles. Common drug related toxicities are outlined in the table below. Four patients experienced serious adverse experiences that were considered not related to MK-2461. PK analysis revealed a rapid Tmax (1-3 hr) across all dosing cohorts with a terminal half life of 6.3 hr following the final day of dosing for the QD dosing cohort. Conclusions: Twice daily administration of MK-2461 at the doses tested is well tolerated. Terminal t1/2 suggests acceptable drug plasma concentrations expected at BID dosing. Dose escalation continues. (source: J Clin Oncol 26: 2008 (May 20 suppl; abstr 14657)
Phase I study of MK-2461:
1. Pan, Bo-Sheng; Chan, Grace K. Y.; Chenard, Melissa; Chi, An; Davis, Lenora J.; Deshmukh, Sujal V.; Gibbs, Jackson B.; Gil, Susana; Hang, Gaozhen; Hatch, Harold; Jewell, James P.; Kariv, Ilona; Katz, Jason D.; Kunii, Kaiko; Lu, Wei; Lutterbach, Bart A.; Paweletz, Cloud P.; Qu, Xianlu; Reilly, John F.; Szewczak, Alexander A.; Zeng, Qinwen; Kohl, Nancy E.; Dinsmore, Christopher J. MK-2461, a Novel Multitargeted Kinase Inhibitor, Preferentially Inhibits the Activated c-Met Receptor. Cancer Research (2010), 70(4), 1524-1533.
2. Burgess, Theresa L.; Coxon, Angela; Dussault, Isabelle; Kaplan-Lefko, Paula; Polverino, Anthony J.; Beaupre, Darrin. Combinations VEGF(R) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer. PCT Int. Appl. (2009), 83pp. CODEN: PIXXD2 WO 2009140549
3. Tomillero A; Moral M A Gateways to clinical trials. Methods and findings in experimental and clinical pharmacology (2009), 31(1), 47-57.