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MK-8033

MK-8033 : ATP competitive inhibitor of MET and MST1R

Structure

Information

  • MET
  • MST1R
  • Inhibitor, ATP Competitive
  • 1-10 uM

In Vitro Validations

Uniprot ID: P08581
Target Class: Kinase
Target SubClass: TK
Potency: IC 50
Potency Value: 1 nM
Potency Assay: In Vitro Kinase Assays
PDB ID for probe-target interaction (3D structure): 4IWD
Structure-activity relationship: yes
Target aliases:
Hepatocyte growth factor receptor, MET, MET_HUMAN, ...

DOI Reference: 10.1021/jm301619u

Uniprot ID: P08581
Target Class: Kinase
Target SubClass: TK
Potency: Kd
Potency Value: 3.2 nM
Potency Assay: BIAcore-based direct binding assay.
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Hepatocyte growth factor receptor, MET, MET_HUMAN, ...

DOI Reference: 10.1021/jm301619u

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

Kinase selectivity @ 1 μmol/L was tested using 221 kinases by Millipore and only MET and MST1R, were inhibited by more than 90%, 4 other kinases (Fes, FGFR3, Flt4, Mer) were inhibited by more than 50%, with the inhibition ranging from 60 to 70%. Titration experiments demonstrated that MK-8033 is >100-fold selective relative to MST1R and MET inhibition versus the measured kinome.

Mutant Potency (nM): MET 1.3 WT, 2.0 N1100Y, 1.0 Y1230C, 0.6 Y1230H, 0.6 Y1235D, 1.2 M1250T

Outside target family:: weak inhibitor of cytochrome P450s at high μM concentrations (IC50s > 11 μM)

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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

The compound is a potent dual-active cMET-MST1R (Ron) kinase inhibitor.  >100 fold selectivity vs a broad kinome panel is presented, but no other broad selectivity is shown.  The molecule is 7 fold selective for cMET vs MST1R.  cMet effects are observed in cells and in vivo but no MST1R effects have been noted or apparently looked for.  A high dose is required for on-target effects in mice.  Any observed effects in vitro or in vitro may be due to cMet, MST1R, or both, and further deconvolution would be required.

NOTE: this molecule is described as a promiscuous inhibitor in this paper https://pubs.acs.org/doi/10.1021/acs.jcim.6b00122, but this appears to be the result of a misinterpretation of % inhibition data as % remaining activity.

(last updated: 19 Jun 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

MK-8033 has preferential binding to the activated kinase conformation of the MET protein.

(last updated: 15 Aug 2021 )