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Reagents and instruments for immunology, cell biology and molecular biology.

Adagrasib [2326521-71-3]

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Cat# HY-130149-10mg

Size : 10mg

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Phone : +1 850 650 7790

Brand : MedChemExpress

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Description

Adagrasib (MRTX849) is a potent, orally-available, and mutation-selective covalent inhibitor of KRAS G12C with potential antineoplastic activity. Adagrasib covalently binds to KRAS G12C at the cysteine at residue 12, locks the protein in its inactive GDP-bound conformation, and inhibits KRAS-dependent signal transduction^[1]^[2].

IC₅₀ & Target

KRas G12C

Cellular Effect

Cell Line	Type	Value	Description	References
A549	IC₅₀	12.9 μM Compound: 3; MRTX849	Antiproliferative activity against human A549 cells harboring KRAS G12S mutant assessed as inhibition of cell proliferation incubated for 3 days by CCK8 assay Antiproliferative activity against human A549 cells harboring KRAS G12S mutant assessed as inhibition of cell proliferation incubated for 3 days by CCK8 assay	[PMID: 36395648]
AGS	IC₅₀	1.4 μM Compound: MRTX849	Antiproliferative activity against human AGS cells assessed as reduction in cell viability measured after 3 days by Celltiter-Glo assay Antiproliferative activity against human AGS cells assessed as reduction in cell viability measured after 3 days by Celltiter-Glo assay	[PMID: 34965125]
MIA PaCa-2	IC₅₀	0.05 μM Compound: 3; MRTX849	Antiproliferative activity against human MIA PaCa-2 cells harboring KRAS G12C mutant assessed as inhibition of cell proliferation incubated for 3 days by CCK8 assay Antiproliferative activity against human MIA PaCa-2 cells harboring KRAS G12C mutant assessed as inhibition of cell proliferation incubated for 3 days by CCK8 assay	[PMID: 36395648]
MIA PaCa-2	IC₅₀	0.1 μM Compound: 17, MRTX849	Antiproliferative activity against human MIA PaCa-2 cells Antiproliferative activity against human MIA PaCa-2 cells	[PMID: 32910655]
MIA PaCa-2	IC₅₀	3.92 nM Compound: MRTX849	Antiproliferative activity against human MIA PaCa-2 cells assessed as inhibition of cell growth incubated for 72 hrs by cell count reagent SF based assay Antiproliferative activity against human MIA PaCa-2 cells assessed as inhibition of cell growth incubated for 72 hrs by cell count reagent SF based assay	[PMID: 37393576]
MIA PaCa-2	IC₅₀	4 nM Compound: MRTX849	Antiproliferative activity against human MIA PaCa-2 cells assessed as reduction in cell viability measured after 3 days by Celltiter-Glo assay Antiproliferative activity against human MIA PaCa-2 cells assessed as reduction in cell viability measured after 3 days by Celltiter-Glo assay	[PMID: 34965125]
MIA PaCa-2	IC₅₀	5 nM Compound: 20; MRTX849	Inhibition of KRAS G12C mutant in human MIAPaCa2 cells assessed as reduction in ERK phosphorylation incubated for 24 hrs by in-cell western method Inhibition of KRAS G12C mutant in human MIAPaCa2 cells assessed as reduction in ERK phosphorylation incubated for 24 hrs by in-cell western method	[PMID: 32250617]
NCI-H1975	IC₅₀	6.37 μM Compound: 3; MRTX849	Antiproliferative activity against human NCI-H1975 cells harboring wild-type KRAS assessed as inhibition of cell proliferation incubated for 3 days by CCK8 assay Antiproliferative activity against human NCI-H1975 cells harboring wild-type KRAS assessed as inhibition of cell proliferation incubated for 3 days by CCK8 assay	[PMID: 36395648]
NCI-H358	IC₅₀	0.001 μM Compound: MRTX-849	Antiproliferative activity against human NCI-H358 cells harboring KRAS G12C mutant assessed as inhibition of cell growth Antiproliferative activity against human NCI-H358 cells harboring KRAS G12C mutant assessed as inhibition of cell growth	[PMID: 36621179]
NCI-H358	IC₅₀	0.006 μM Compound: 2	Antiproliferative activity against human NCI-H358 cells harboring KRAS G12C mutant cultured as 3D spheroids assessed as reduction in cell proliferation incubated for 3 days by CellTiter-Glo 3D reagent based assay Antiproliferative activity against human NCI-H358 cells harboring KRAS G12C mutant cultured as 3D spheroids assessed as reduction in cell proliferation incubated for 3 days by CellTiter-Glo 3D reagent based assay	[PMID: 37395055]
NCI-H358	IC₅₀	0.02 μM Compound: 3; MRTX849	Antiproliferative activity against human NCI-H358 cells harboring KRAS G12C mutant assessed as inhibition of cell proliferation incubated for 3 days by CCK8 assay Antiproliferative activity against human NCI-H358 cells harboring KRAS G12C mutant assessed as inhibition of cell proliferation incubated for 3 days by CCK8 assay	[PMID: 36395648]
NCI-H358	IC₅₀	14 nM Compound: 20; MRTX849	Inhibition of KRAS G12C mutant in human NCI-H358 cells assessed as reduction in ERK phosphorylation incubated for 3 hrs by in-cell western method Inhibition of KRAS G12C mutant in human NCI-H358 cells assessed as reduction in ERK phosphorylation incubated for 3 hrs by in-cell western method	[PMID: 32250617]
NCI-H358	IC₅₀	6 nM Compound: MRTX849	Antiproliferative activity against human NCI-H358 cells assessed as reduction in cell viability measured after 3 days by Celltiter-Glo assay Antiproliferative activity against human NCI-H358 cells assessed as reduction in cell viability measured after 3 days by Celltiter-Glo assay	[PMID: 34965125]
NCI-H358	IC₅₀	9.2 nM Compound: MRTX849	Antiproliferative activity against human NCI-H358 cells harboring KRAS p.G12C mutant assessed as inhibition of cell growth incubated for 72 hrs by cell count reagent SF based assay Antiproliferative activity against human NCI-H358 cells harboring KRAS p.G12C mutant assessed as inhibition of cell growth incubated for 72 hrs by cell count reagent SF based assay	[PMID: 37393576]
PaTu 8988t	IC₅₀	3 μM Compound: MRTX849	Antiproliferative activity against human PaTu 8988t cells assessed as reduction in cell viability measured after 3 days by Celltiter-Glo assay Antiproliferative activity against human PaTu 8988t cells assessed as reduction in cell viability measured after 3 days by Celltiter-Glo assay	[PMID: 34965125]

In Vitro

Adagrasib (MRTX849) (0.1-10000 nM; 3-day/2D conditions; 12-day/3D conditions) potently inhibits cell growth in the vast majority of KRAS G12C-mutant cell lines with IC₅₀s ranging between 10 and 973 nM in the 2D format and between 0.2 and 1042 nM in the 3D format^[1].
Adagrasib (0.24-1000 nM; 24 hours) inhibits KRAS-dependent signaling targets including ERK1/2 phosphorylation (Thr202/Tyr204 ERK1; pERK), S6 phosphorylation (RSK-dependent Ser235/236; pS6) and expression of the ERK-regulated DUSP6^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Viability Assay^[1]

Cell Line:	MIA PaCa-2, H1373, H358, H2122, SW1573, H2030, KYSE-410 cells (G12C); H1299 (WT); A549 (G12S), HCT116 (G13D) cells
Concentration:	0.1, 1, 10, 100, 1000, 10000 nM
Incubation Time:	24 hours
Result:	Inhibits cell growth in the vast majority of KRAS G12C-mutant cell lines with IC₅₀ values ranging between 10 and 973 nM in the 2D format and between 0.2 and 1042 nM in the 3D format.

Western Blot Analysis^[1]

Cell Line:	MIA PaCa-2 cells
Concentration:	0.24, 0.5, 1.0, 2.0, 3.9, 7.8, 15.6, 31.3, 62.5, 125, 250, 500, 1000 nM
Incubation Time:	24 hours
Result:	Inhibits KRAS-dependent signaling targets including ERK1/2 phosphorylation (Thr202/Tyr204 ERK1; pERK), S6 phosphorylation (RSK-dependent Ser235/236; pS6) and expression of the ERK-regulated DUSP6, each with IC₅₀s in the single-digit nanomolar range in cell lines.

In Vivo

Adagrasib (1-100 mg/kg; i.g.; daily until day 16) demonstrates dose-dependent anti-tumor efficacy over a well-tolerated dose range, and the maximally efficacious dose of MRTX849 is between 30-100 mg/kg/day^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model:	MIA PaCa-2 model (6-8-week-old, female, athymic nude-Foxn1 nu mice)^[1]
Dosage:	1, 3, 10, 30 and 100 mg/kg
Administration:	Oral gavage; daily until Day 16
Result:	Rapid tumor regression was observed at the earliest posttreatment tumor measurement and animals in the 30 and 100 mg/kg cohorts exhibited evidence of a complete response at study Day 15. Dosing was stopped at study Day 16 and all 4 mice in the 100 mg/kg cohort and 2 out of 7 mice in the 30 mg/kg cohort remained tumor-free through study Day 70.

Clinical Trial

Molecular Weight

604.12

Formula

C₃₂H₃₅ClFN₇O₂

CAS No.

2326521-71-3

Appearance

Solid

Color

White to yellow

SMILES

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

Shipping

Room temperature in continental US; may vary elsewhere.

Storage

Powder	-20°C	3 years
	4°C	2 years
In solvent	-80°C	6 months
	-20°C	1 month

Solvent & Solubility

In Vitro:

DMSO : 25 mg/mL (41.38 mM; ultrasonic and warming and heat to 60°C; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

Preparing
Stock Solutions

Concentration Solvent Mass	1 mg	5 mg	10 mg

1 mM	1.6553 mL	8.2765 mL	16.5530 mL
5 mM	0.3311 mL	1.6553 mL	3.3106 mL
10 mM	0.1655 mL	0.8277 mL	1.6553 mL

View the Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

Select the appropriate dissolution method based on your experimental animal and administration route.

For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

Protocol 1

Add each solvent one by one: 5% DMSO 40% PEG300 5% Tween-80 50% Saline
Solubility: ≥ 2.62 mg/mL (4.34 mM); Clear solution
Protocol 2

Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline
Solubility: ≥ 2.5 mg/mL (4.14 mM); Clear solution

This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
Protocol 3

Add each solvent one by one: 10% DMSO 90% Corn Oil
Solubility: ≥ 2.5 mg/mL (4.14 mM); Clear solution

This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown). If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL Corn oil, and mix evenly.

Purity & Documentation

Purity: 99.96%

Data Sheet (284 KB) SDS (393 KB)

COA (257 KB) HNMR (148 KB) RP-HPLC (225 KB) MS (68 KB)

Handling Instructions (2659 KB)

References

[1]. Christensen JG, et al. The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2019 Oct 28. pii: CD-19-1167. [Content Brief]

[2]. Kyriakos P. Papadopoulos, et al. A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation. Journal of Clinical Oncology 2019 37:15_suppl, TPS3161-TPS3161.

[3]. Fell JB, Fischer JP, Baer BR, et al. Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer. J Med Chem. 2020;63(13):6679-6693. [Content Brief]

[4]. Awad MM, Liu S, Rybkin II, et al. Acquired Resistance to KRASG12C Inhibition in Cancer. N Engl J Med. 2021;384(25):2382-2393. [Content Brief]

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