MRTX849

Protein target name:

KRAS G12C

Mechanism of action:

Covalent InhibitorMutant G12C Specific

Recommended Concentration for use in cells:

~~up to 500 nM~~

Reviewer suggested Concentration for use in cells:

up to 100 nM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Subclass:

GTPase

HUGO ID:

HGNC:6407

Entrez gene ID:

3845

UNIPROT ID:

P01116

Target alias:

NS; NS3; OES; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; C-K-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; K-Ras 2; 'C-K-RAS; c-Ki-ras; c-Ki-ras

Probe Details

Chemical Probes Portal ID:

CPP1857

Probe alias:

Compound 20

PubChem CID:

138611145

SMILES string:

N#CC[C@@H]1N(C(C(F)=C)=O)CCN(C2=C3C(CN(C4=C5C(Cl)=CC=CC5=CC=C4)CC3)=NC(OC[C@H]6N(C)CCC6)=N2)C1

InChi Key:

PEMUGDMSUDYLHU-ZEQRLZLVSA-N

Control compound:

Compound-21

Orthogonal probe:

ARS-1620AMG-510

Physico-chemical properties

NMR:

1H NMR (400 MHz, CDCl3) δ 7.76 (td, J = 1.6, 8.0 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.45 (td, J = 7.6, 13.2 Hz, 1H), 7.37–7.31 (m, 1H), 7.27–7.18 (m, 1H), 5.51–5.33 (m, 1H), 5.25 (dd, J = 3.6, 16.8 Hz, 1H), 5.10–4.58 (m, 1H), 4.48–4.35 (m, 2H), 4.19–4.01 (m, 3H), 3.99–3.74 (m, 2H), 3.63–3.56 (m, 1H), 3.43 (br d, J = 12.8 Hz, 1H), 3.30–3.02 (m, 5H), 2.96–2.74 (m, 2H), 2.72–2.53 (m, 2H), 2.48 (d, J = 2.0 Hz, 3H), 2.28 (ddt, J = 2.0, 7.2, 9.6 Hz, 1H), 2.12–1.99 (m, 1H), 1.88–1.69 (m, 3H);

13C NMR (100 MHz, CDCl3): δ 166.3, 166.1, 75 162.6, 158.0, 155.3, 148.4, 148.0, 137.2, 130.0, 129.6, 128.2, 126.4, 125.9, 125.6, 125.1, 124.9, 118.5, 116.7, 109.2, 101.4, 69.9, 63.8, 59.0, 58.6, 57.6, 50.3, 48.0, 41.7, 29.1, 26.1, 25.4, 22.9;

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

Kobs

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

In cell validation

On target activity in cells

Potency in cells:

IC50

14 nM, 4.7 nM (24h)

Potency assay (cells):

NCI-H358 cellular pERK inhibition at 3 h

In vivo validation

Organism:

MouseRatDog

Dose:

3 mg/Kg IV3 to 100 mg/Kg PO

Route of delivery:

OralIntravenous

Plasma half life:

1.51 (M), 2.57 (R), 7.56 (D) h

Systemic clearance:

19.9 (M), 44.2 (R), 29.6 (D) ml/min/kg

Fraction of probe bound to plasma protein:

62.929.725.9

Cmax:

2.41 (M), 0.209 (R), 0.252 (D) ug/ml

Tmax:

1.0 (M), 2.67 (R), 4.0 (D) h

Organ of Interest

Target engagement assay:

Anti-tumor activity of MRTX849 was evaluated in a MIA PaCa-2 xenograft model.

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.9b02052 10.1158/2159-8290.CD-19-1167

Reference (PMID):

32250617 31658955

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB 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.

Aug 4 2020 - 1:22pm

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.

Sep 5 2020 - 8:38am

MRTX849

Probe Availability

Probe Information

Target Details

NS; NS3; OES; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; C-K-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; K-Ras 2; 'C-K-RAS; c-Ki-ras; c-Ki-ras

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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MRTX849

Probe Availability

Probe Information

Target Details

NS; NS3; OES; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; C-K-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; K-Ras 2; 'C-K-RAS; c-Ki-ras; c-Ki-ras

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?