MRTX849

Covalent Inhibitor of KRAS (Mutant:G12C)

Structure

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In Cells

(3 ratings)

In Model Organisms

(3 ratings)

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Information

KRAS (Mutant:G12C)

Covalent Inhibitor

~~up to 500 nM~~
Reviewer recommended concentration: up to 100 nM

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Probe Availability:

In Vitro Validations

Uniprot ID: P01116

Target Class: Other

Target SubClass: GTPase

Potency: Kobs

Potency Value: low uM

Potency Assay: LCMS measurement of the pepsin-derived Cys12-containing peptide fragments

PDB ID for probe-target interaction (3D structure): 6UTO, 6USX, 6USZ

Structure-activity relationship: yes

Target aliases:

GTPase KRas, RASK2, KRAS2, KRAS, RASK_HUMAN, c-Ki- ...

DOI Reference: 10.1021/acs.jmedchem.9b02052

In Cell Validations

In Vivo Data

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

(last updated: 25 Jul 2020 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

MRTX849 is a very potent and selective inhibitor of kRas G12C. Along with AMG-510 this compound is one of the first to proceed through clinical development showing benefit in certain tumor types that harbor a G12C mutation. The on-target cellular potency and selectivity has been robustly established, validated and published. Across a wide range of cell lines G12C mutations, MRTX849 shows low nM inhibition of pERK as well as 2D/3D antiproliferation activity. MRTX849 can also be used in vivo with oral dosing where dose dependent inhibition pERK and other pathway markers as well as tumor growth inhibition or regression in more sensitive models is observed.
The electrophilicity of the olefin which traps the cysteine in G12C was carefully modulated and cysteinomics have shown an overall very clear profile.
A negative control such as a version where the electrophilic warhead is reduced would be a nice complement to the package.

(last updated: 4 Aug 2020 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

MRTX849:

- Is a potent, orally-available, and mutation-selective covalent inhibitor of KRAS G12C presently undergoing phaseI/II clinical trials in patients with non-small cell lung cancer. MRTX849 covalently binds to KRAS G12C at the cysteine residue 12 and locks the protein in its inactive GDP bound conformation.

- It inhibits KRAS-dependent ERK1/2 phosphorylation with IC50 in the single-digit nanomolar range in cellular assays and inhibits cell viability in most KRAS G12C-mutant cell lines with IC50 between 10 and 1000 nM in the 2D format and between 0.2 and 1000 nM in the 3D format.

- Demonstrates pronounced tumor regression in 17 of 26 KRAS G12C -positive cell line– and patient-derived xenograft models from multiple tumor types.

- Highly specific to KRASG12C in the NCI-H358 proteome at a concentration of 1 μM using MS proteomics studies.

- There is no real in vitro biochemical assay validation possible due to the covalent nature of inhibitor. In cell p-ERK assay (in cell close to target assay) is used instead.

(last updated: 5 Sept 2020 )