| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
| Targets |
Active (GTP-bound) KRAS G12C mutant. RMC-4998 is a highly selective inhibitor that targets the active, GTP-bound conformation of the KRAS G12C oncogenic mutant. It does not inhibit wild-type KRAS, NRAS, or HRAS, indicating high mutant selectivity.
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|---|---|
| ln Vitro |
RMC-4998 is a potent inhibitor of the active KRAS G12C mutant, with an IC50 of 28 nM for ternary complex formation. In cell-based assays, it selectively inhibits the proliferation of KRAS G12C mutant cells with a mean IC50 of 0.28 nM. It shows no activity against wild-type KRAS, NRAS, or HRAS, confirming its exquisite selectivity.
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| ln Vivo |
In H358 non-small cell lung cancer (NSCLC) xenograft mouse models, oral administration of RMC-4998 significantly inhibits tumor growth and induces tumor regression. This is accompanied by suppression of the ERK pathway and induction of apoptosis. In vivo efficacy is also observed at 80 mg/kg daily for 4 weeks in NSCLC mice, promoting tumor regression.
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| Enzyme Assay |
A cell-free assay for RMC-4998 is performed using surface plasmon resonance (SPR) or a biochemical ternary complex formation assay. Purified, activated KRAS G12C and recombinant CYPA are incubated with varying concentrations of RMC-4998. Complex formation is detected using labeled antibodies, and the IC50 (28 nM) for promoting the ternary complex is calculated.
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| Cell Assay |
For cellular assays, KRAS G12C-mutant cell lines (e.g., NCI-H358, MIA PaCa-2) are seeded in 96-well plates and treated with RMC-4998 (0.1 pM to 100 nM) for 72 hours. Cell viability is assessed using CellTiter-Glo to determine the mean IC50 (0.28 nM). For signaling studies, cells are treated with compounds, lysed, and analyzed by Western blot for p-ERK and cleaved PARP.
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| Animal Protocol |
In vivo efficacy is evaluated in mouse xenograft models of KRAS G12C NSCLC. Nude mice are implanted subcutaneously with NCI-H358 cells. When tumors reach ~100-200 mm3, RMC-4998 is administered orally at doses of 30-100 mg/kg daily. Tumor volume is measured with calipers. At study termination, tumors are harvested for IHC analysis of p-ERK and Ki-67 (proliferation marker).
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| ADME/Pharmacokinetics |
RMC-4998 is orally bioavailable. In preclinical studies, oral administration leads to significant tumor exposure and sustained inhibition of the KRAS G12C target. The compound is typically dosed once daily in mouse models, with good correlation between plasma concentration and tumor growth inhibition.
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| Toxicity/Toxicokinetics |
Not reported. The toxicological profile of RMC-4998 in animal models appears favorable, as it is well-tolerated at efficacious doses (up to 100 mg/kg daily) in mice. On-target toxicities are expected to be related to KRAS G12C inhibition and are likely limited to mutant-expressing tissues, as it is highly selective for the mutant over the wild-type RAS isoforms.
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| References |
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| Additional Infomation |
RMC-4998 is a next-generation KRAS G12C inhibitor developed by Revolution Medicines. Unlike first-generation inhibitors (e.g., sotorasib, adagrasib) that target the inactive (GDP-bound) state, RMC-4998 targets the active (GTP-bound) state of KRAS G12C. This allows it to be effective in tumors that have developed resistance to first-generation inhibitors via mechanisms that keep KRAS in its active state. It is currently in preclinical development and represents a promising strategy to overcome acquired resistance in KRAS G12C-driven cancers.
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| Molecular Formula |
C57H74N8O7
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|---|---|
| Molecular Weight |
983.246874332428
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| Exact Mass |
982.568
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| CAS # |
2642037-07-6
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| PubChem CID |
156335332
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| Appearance |
White to off-white solid powder
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| LogP |
6.7
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
72
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| Complexity |
2050
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| Defined Atom Stereocenter Count |
5
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| SMILES |
CCN1C2=C3C=C(C=C2)C4=CC=CC(=C4)C[C@@H](C(=O)N5CCC[C@H](N5)C(=O)OCC(CC3=C1C6=C(N=CC=C6)[C@H](C)OC)(C)C)NC(=O)[C@H](C(C)C)N7CC[C@@]8(C7=O)CCN(C8)C(=O)C#CC(C)(C)N(C)C
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| InChi Key |
VYZILERTWJIGRC-DOESOIHZSA-N
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| InChi Code |
InChI=1S/C57H74N8O7/c1-12-63-46-21-20-40-32-42(46)43(50(63)41-18-14-26-58-48(41)37(4)71-11)33-55(5,6)35-72-53(69)44-19-15-27-65(60-44)52(68)45(31-38-16-13-17-39(40)30-38)59-51(67)49(36(2)3)64-29-25-57(54(64)70)24-28-62(34-57)47(66)22-23-56(7,8)61(9)10/h13-14,16-18,20-21,26,30,32,36-37,44-45,49,60H,12,15,19,24-25,27-29,31,33-35H2,1-11H3,(H,59,67)/t37-,44-,45-,49-,57-/m0/s1
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| Chemical Name |
(2S)-2-[(5S)-7-[4-(dimethylamino)-4-methylpent-2-ynoyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(8S,14S)-22-ethyl-21-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]-3-methylbutanamide
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0170 mL | 5.0852 mL | 10.1704 mL | |
| 5 mM | 0.2034 mL | 1.0170 mL | 2.0341 mL | |
| 10 mM | 0.1017 mL | 0.5085 mL | 1.0170 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.
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