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Purity: = 100%
Adagrasib (MRTX-849; Krazati) is a newly approved, selective, orally bioavailable and covalent / irreversible inhibitor of KRAS G12C with IC50s ranging between 10 and 973 nM in the 2D format and between 0.2 and 1042 nM in the 3D format. It functions by covalently binding to KRAS G12C at the cysteine at residue 12, locking the protein in its inactive GDP-bound conformation, and preventing KRAS-dependent signal transduction. This may have antineoplastic properties. Adagrasib (Krazati), a RAS GTPase family inhibitor developed by Mirati Therapeutics, Inc., has received accelerated approval by the US Food and Drug Administration (FDA) as of December 12, 2022, for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that has a KRAS G12C mutation.
| Targets |
K-Ras(G12C)
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|---|---|
| ln Vitro |
MRTX849's impact on cell viability is assessed using 2D (3-day adherent cells) and 3D (12-day spheroids) cell growth conditions on a panel of 17 KRASG12C-mutant and three non-KRASG12C-mutant cancer cell lines in order to assess the range of its activity. IC50 values of MRTX849 range from 10 nM to 973 nM in 2D format and from 0.2 nM to 1042 nM in 3D format, indicating that it potently inhibits cell growth in the majority of KRASG12C-mutant cell lines[1].
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| ln Vivo |
At the 15th study day, animals in the 30 mg/kg and 100 mg/kg cohorts show signs of a full response, and rapid tumor regression is seen at the earliest posttreatment tumor measurement. Four mice in the 100 mg/kg cohort and two out of seven mice in the 30 mg/kg cohort remain tumor-free until study day 70. The dose is stopped at study day 16.[1]
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| Enzyme Assay |
KRASG12C Target Engagement[2]
Tumor fragments were homogenized in 6 M guanidine–HCl, 50 mM N-(2-hydroxyethyl)piperazine-N′-ethanesulfonic acid (HEPES) (pH 7.5), and 5 mM TCEP. Following centrifugation, the protein concentration of the supernatant was determined using a Bradford assay. An internal standard (13C15N recombinant KRASG12C) and 20 mM iodoacetamide were added to 200 μg of tumor protein in 200 μL of lysis buffer, and samples were incubated at 37 °C for 30 min in the dark. Following alkylation, 100 μL of the reaction was exchanged into 1 M guanidine–HCl, 50 mM HEPES (pH 7.5), using a 96-well Zeba spin plate. Proteins were digested with 1 μg of trypsin/Lys-C mix at 37 °C for 18 h. Peptides were desalted using a C18 spin plate, and the solvent was removed by evaporation. Peptides were solubilized in 0.1% formic acid, 5% acetonitrile, 95% water, for LCMS analysis. A targeted method on a Sciex TripleTOF instrument was used to monitor the Cys-12-containing KRASG12C peptide, an internal reference peptide, as well as the corresponding isotope-labeled peptides. KRASG12C engagement was calculated as previously reported.[2] Measurement of kinact/KI[2] Recombinant KRASG12C “Lite” (C51S/C80L/C118S) was reacted with a range of MRTX849 concentrations in 25 mM HEPES (pH 7.0), 150 mM NaCl, 5 mM MgCl2, 10 mM octyl β-glucopyranoside, and 0.5 mM TCEP, for 0–45 s, at room temperature. At each time-point, the reaction was quenched with 50 mM HCl, and 0.25 μg of pepsin was added. KRASG12C was digested for 4 h at 37 °C, and the resulting Cys-12-containing peptide was analyzed by LCMS. The percent of modified KRASG12C at each time-point was calculated from the 0 s control sample for each concentration of MRTX849, and kobs was subsequently calculated from the slope of the ln(POC) versus time data. Rate versus concentration data fit the Michaelis–Menten equation. |
| Cell Assay |
All cell lines were kept in a humidified incubator with 5% CO2 at 37 °C, and their mycoplasma levels were routinely examined. Cell viability was assessed using the CellTiter-Glo assay on seven KRAS G12C-mutant cell lines and three non-KRAS G12C-mutant cell lines that were grown in either 3D conditions using 96-well ULA plates in a 12-day assay or 2D tissue culture conditions in a 3-day assay.
Cell Viability Assay[1] Cell Types: MIA PaCa-2, H1373, H358, H2122, SW1573, H2030, KYSE-410 cells (G12C); H1299 (WT); A549 (G12S), HCT116 (G13D) cells Tested Concentrations: 0.1, 1, 10, 100, 1000, 10000 nM Incubation Duration: 24 h Experimental Results: 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 Types: MIA PaCa-2 cells Tested Concentrations: 0.24, 0.5, 1.0, 2.0, 3.9, 7.8, 15.6, 31.3, 62.5, 125, 250, 500, 1000 nM Incubation Duration: 24 h Experimental Results: 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. |
| Animal Protocol |
Animal/Disease Models: MIA PaCa-2 model (6-8-week-age, female, athymic nude-Foxn1 nu mice)[1]
Doses: 1, 3, 10, 30, 100 mg/kg Route of Administration: p.o., for 16 days, daily Experimental Results: 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. |
| References |
| Molecular Formula |
C32H35CLFN7O2
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|---|---|
| Molecular Weight |
604.1274
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| Exact Mass |
603.25
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| Elemental Analysis |
C, 63.62; H, 5.84; Cl, 5.87; F, 3.14; N, 16.23; O, 5.30
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| CAS # |
2326521-71-3
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| Related CAS # |
MRTX849 analog 24; 2490716-96-4; LC-2; 2502156-03-6
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| Appearance |
Solid powder
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| LogP |
5
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| tPSA |
88.8Ų
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| SMILES |
CN1CCC[C@H]1COC2=NC3=C(CCN(C3)C4=CC=CC5=C4C(=CC=C5)Cl)C(=N2)N6CCN([C@H](C6)CC#N)C(=O)C(=C)F
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| InChi Key |
PEMUGDMSUDYLHU-ZEQRLZLVSA-N
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| InChi Code |
InChI=1S/C32H35ClFN7O2/c1-21(34)31(42)41-17-16-40(18-23(41)11-13-35)30-25-12-15-39(28-10-4-7-22-6-3-9-26(33)29(22)28)19-27(25)36-32(37-30)43-20-24-8-5-14-38(24)2/h3-4,6-7,9-10,23-24H,1,5,8,11-12,14-20H2,2H3/t23-,24-/m0/s1
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| Chemical Name |
2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile
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| Synonyms |
Adagrasib; MRTX 849; MRTX849; MRTX-849; brand name: Krazati
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 25~100 mg/mL (41.4~165.5 mM)
Ethanol: ~100 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.62 mg/mL (4.34 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.14 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.14 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: in 5%DMSO+ 40%PEG300+ 5%Tween 80+ 50%ddH2O: 5.0mg/ml (8.28mM) (add these co-solvents sequentially from left to right, and one by one), |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6553 mL | 8.2764 mL | 16.5527 mL | |
| 5 mM | 0.3311 mL | 1.6553 mL | 3.3105 mL | |
| 10 mM | 0.1655 mL | 0.8276 mL | 1.6553 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05853575 | Recruiting | Drug: Adagrasib | Advanced Cancer Metastatic Cancer |
Mirati Therapeutics Inc. | April 5, 2023 | Phase 2 |
| NCT06039384 | Recruiting | Drug: INCB099280 Drug: adagrasib |
Advanced Solid Tumors | Incyte Corporation | December 28, 2023 | Phase 1 |
| NCT05840510 | Recruiting | Drug: Adagrasib Drug: nab-Sirolimus |
NSCLC | Mirati Therapeutics Inc. | August 7, 2023 | Phase 1 Phase 2 |
| NCT06130254 | Not yet recruiting | Drug: Adagrasib Drug: Olaparib |
Non-small Cell Lung Cancers Advanced Solid Tumor |
M.D. Anderson Cancer Center | May 31, 2024 | Phase 1 |
| NCT05673187 | Recruiting | Drug: Adagrasib | NSCLC Stage IV KRAS P.G12C |
ETOP IBCSG Partners Foundation | June 12, 2023 | Phase 2 |
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