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MedKoo Cat#: 525682 | Name: MK-2461
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

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-kinase–AKT and Ras–extracellular signal-regulated kinase pathways, without inhibiting autophosphorylation of the c-Met activation loop. In cell culture, MK-2461 inhibited hepatocyte growth factor/c-Met–dependent mitogenesis, migration, cell scatter, and tubulogenesis. In a murine xenograft model of c-Met–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):1524–33)

Chemical Structure

MK-2461
MK-2461
CAS#917879-39-1

Theoretical Analysis

MedKoo Cat#: 525682

Name: MK-2461

CAS#: 917879-39-1

Chemical Formula: C24H25N5O5S

Exact Mass: 495.1576

Molecular Weight: 495.55

Elemental Analysis: C, 58.17; H, 5.09; N, 14.13; O, 16.14; S, 6.47

Price and Availability

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5mg USD 450.00 2 weeks
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Related CAS #
No Data
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
Appearance
Solid powder
Purity
>98%
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>5 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
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: (source:  
Product Data
Product Data
Instruction
View handling instruction
Biological target:
MK-2461 is a novel ATP-competitive multitargeted inhibitor of activated c-Met with a mean IC50 of 2.5 nM.
In vitro activity:
In PSCs (pancreatic stellate cells), PDGFRβ and MET (hepatocyte growth factor receptor) were upregulated compared with other receptor tyrosine kinases. Conditioned medium from PSCs promoted the proliferation of PCCs (pancreatic cancer cells), and vice versa. Moreover, MK2461 suppressed the effects of conditioned medium on PCCs and PSCs. Reference: Pancreas. 2017 Apr;46(4):557-566. https://pubmed.ncbi.nlm.nih.gov/28196027/
In vivo activity:
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-kinase-AKT and Ras-extracellular signal-regulated kinase pathways, without inhibiting autophosphorylation of the c-Met activation loop. MK-2461 displayed significant inhibitory activities against fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor, and other receptor tyrosine kinases. In cell culture, MK-2461 inhibited hepatocyte growth factor/c-Met-dependent mitogenesis, migration, cell scatter, and tubulogenesis. Reference: Cancer Res. 2010 Feb 15;70(4):1524-33. https://pubmed.ncbi.nlm.nih.gov/20145145/
Solvent mg/mL mM comments
Solubility
DMSO 53.3 107.62
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 495.55 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
1. Inoue K, Ohtsuka H, Tachikawa M, Motoi F, Shijo M, Douchi D, Kawasaki S, Kawaguchi K, Masuda K, Fukase K, Naitoh T, Katayose Y, Egawa S, Unno M, Terasaki T. MK2461, a Multitargeted Kinase Inhibitor, Suppresses the Progression of Pancreatic Cancer by Disrupting the Interaction Between Pancreatic Cancer Cells and Stellate Cells. Pancreas. 2017 Apr;46(4):557-566. doi: 10.1097/MPA.0000000000000778. PMID: 28196027. 2. Pan BS, Chan GK, Chenard M, Chi A, Davis LJ, Deshmukh SV, Gibbs JB, Gil S, Hang G, Hatch H, Jewell JP, Kariv I, Katz JD, Kunii K, Lu W, Lutterbach BA, Paweletz CP, Qu X, Reilly JF, Szewczak AA, Zeng Q, Kohl NE, Dinsmore CJ. MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33. doi: 10.1158/0008-5472.CAN-09-2541. Epub 2010 Feb 9. PMID: 20145145.
In vitro protocol:
1. Inoue K, Ohtsuka H, Tachikawa M, Motoi F, Shijo M, Douchi D, Kawasaki S, Kawaguchi K, Masuda K, Fukase K, Naitoh T, Katayose Y, Egawa S, Unno M, Terasaki T. MK2461, a Multitargeted Kinase Inhibitor, Suppresses the Progression of Pancreatic Cancer by Disrupting the Interaction Between Pancreatic Cancer Cells and Stellate Cells. Pancreas. 2017 Apr;46(4):557-566. doi: 10.1097/MPA.0000000000000778. PMID: 28196027. 2. Pan BS, Chan GK, Chenard M, Chi A, Davis LJ, Deshmukh SV, Gibbs JB, Gil S, Hang G, Hatch H, Jewell JP, Kariv I, Katz JD, Kunii K, Lu W, Lutterbach BA, Paweletz CP, Qu X, Reilly JF, Szewczak AA, Zeng Q, Kohl NE, Dinsmore CJ. MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33. doi: 10.1158/0008-5472.CAN-09-2541. Epub 2010 Feb 9. PMID: 20145145.
In vivo protocol:
1. Inoue K, Ohtsuka H, Tachikawa M, Motoi F, Shijo M, Douchi D, Kawasaki S, Kawaguchi K, Masuda K, Fukase K, Naitoh T, Katayose Y, Egawa S, Unno M, Terasaki T. MK2461, a Multitargeted Kinase Inhibitor, Suppresses the Progression of Pancreatic Cancer by Disrupting the Interaction Between Pancreatic Cancer Cells and Stellate Cells. Pancreas. 2017 Apr;46(4):557-566. doi: 10.1097/MPA.0000000000000778. PMID: 28196027. 2. Pan BS, Chan GK, Chenard M, Chi A, Davis LJ, Deshmukh SV, Gibbs JB, Gil S, Hang G, Hatch H, Jewell JP, Kariv I, Katz JD, Kunii K, Lu W, Lutterbach BA, Paweletz CP, Qu X, Reilly JF, Szewczak AA, Zeng Q, Kohl NE, Dinsmore CJ. MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33. doi: 10.1158/0008-5472.CAN-09-2541. Epub 2010 Feb 9. PMID: 20145145.
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.