[CAS NO. 1283000-43-0] MK-8033hydrochloride
PRODUCTS SPECIFICATIONS [1283000-43-0]
DESCRIPTION [1283000-43-0]
Overview
| MDL | MFCD28167721 |
|---|---|
| Molecular Weight | 507.99 |
| Molecular Formula | C25H22ClN5O3S |
| SMILES | O=S(CC1=CC=C2C(C(C3=CC(C4=CN(C)N=C4)=CN=C3C=C2)=O)=C1)(NCC5=NC=CC=C5)=O.Cl |
2 Publications Citing Use of MCE
Summary
MK-8033 hydrochloride is an orally active ATP competitive c-Met/Ron dual inhibitor ( IC 50 s: 1 nM (c-Met),7 nM (Ron)), with preferential binding to the activated kinase conformation. MK-8033 hydrochloride can be used in the research of cancers, such as breast and bladder cancers, non-small cell lung cancers (NSCLCs) [1] [2] .
IC50 & Target
IC50: 7 nM (Ron) [1]
In Vitro
MK-8033 hydrochloride (Compound 11r, 10 μM) displayed 31% inhibition of CYP3A4 (cytochrome P450 3A4)
[1]
.
MK-8033 hydrochloride (1 μM, 2 h) inhibits phosphorylation of Y1349 of c-Met (IC
50
: 0.03 μM) in the c-Met dependent gastric cancer cell line GTL-16
[1]
.
MK-8033 hydrochloride (1-10 μM, 72 h) inhibits GTL-16 cell proliferation (IC
50
: 0.58 μM)
[1]
.
MK-8033 hydrochloride binds more tightly to phosphorylated c-Met (K
d
: 3.2 nM) than to its unphosphorylated counterpart (K
d
: 10.4 nM), and inhibits oncogenic c-Met activation loop mutants with IC
50
s ranging from 0.6 to 1 nM
[1]
.
MK-8033 hydrochloride (0.1-10 μM, 2 h) reduces the phosphorylation of c-Met, ERK, and Akt in EBC-1 and H1993 cells
[2]
.
MK-8033 hydrochloride (1 μM, 1 h) sensitizes EBC-1 and H1993 cells (high c-Met-expressing) to radiation
[2]
.
MK-8033 hydrochloride (10 μM, 6 h) enhances γ-H2Ax levels in A549 cells compared to double irradiation and decreases in DNA repair
[2]
.
MK-8033 hydrochloride (2 μM, 72 h) results in reduced cell proliferation, but modest induction of apoptosis in G-alpha protein mutant UM (uveal melanoma) cells
[3]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Western Blot Analysis [2]
| Cell Line: | EBC-1, H1993 cells, A549 and H460 cells |
| Concentration: | 0.1, 1, 10 μM |
| Incubation Time: | 2 h |
| Result: | Reduced the phosphorylation of c-Met, ERK, and Akt in EBC-1 and H1993 cells in a dose-dependent manner. |
In Vivo
MK-8033 hydrochloride (Compound 11r, oral administration, 3-100 mg/kg, twice daily for 21 days) inhibits tumor growth in GTL-16 c-Met amplified gastric tumor xenografts
[1]
.
MK-8033 hydrochloride exhibits moderate clearance (t
1/2
: 0.8 h for rats, 3.1 h for dog) and favorable bioavailability (35% for rats, 33% for dog)
[1]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
| Animal Model: | Human GTL-16 c-Met amplified gastric tumor xenografts [1] |
| Dosage: | 3, 10, 30, and 100 mg/kg |
| Administration: | Oral administration, twice daily for 21 days |
| Result: |
Resulted in 22, 18, 57, and 86% tumor growth inhibition at 3, 10, 30, and 100 mg/kg, respectively.
Inhibited c-Met (Y1349) phosphorylation. |
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date | Phase |
|---|---|---|---|---|
| NCT00559182 | Merck Sharp & Dohme LLC |
Advanced Cancer
|
December 5, 2007 | Phase 1 |
Appearance
Solid
Shipping
Room temperature in continental US; may vary elsewhere.
Storage
4°C, sealed storage, away from moisture
* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)
Solvent & Solubility
H 2 O : 7.14 mg/mL ( 14.06 mM ; Need ultrasonic)
DMSO : 5.88 mg/mL ( 11.58 mM ; Need ultrasonic)
Stock Solutions
| Concentration Solvent Mass | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 1.9685 mL | 9.8427 mL | 19.6854 mL |
| 5 mM | 0.3937 mL | 1.9685 mL | 3.9371 mL |
| 10 mM | 0.1969 mL | 0.9843 mL | 1.9685 mL |
-
1.
-
2.
Add each solvent one by one: 10% DMSO >> 90% (20% SBE-β-CD in saline)
Solubility: ≥ 0.59 mg/mL (1.16 mM); Clear solution
References
- [1] Northrup AB, et al, 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
- [2] Bhardwaj V, et al. C-Met inhibitor MK-8003 radiosensitizes c-Met-expressing non-small-cell lung cancer cells with radiation-induced c-Met-expression. J Thorac Oncol. 2012 Aug;7(8):1211-7.
- [3] Chandrani Chattopadhyay, et al. Simultaneous inhibition of the HGF/MET and Erk1/2 pathways affect uveal melanoma cell growth and migration. PLoS One. 2014 Feb 13;9(2):e83957.
