| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| Other Sizes |
| Targets |
KRas G12V
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|---|---|
| ln Vitro |
When evaluated in a cellular NanoBRET assay across concentrations from 10⁻¹¹ M to 10⁻⁶ M, RMC-5127 potently interfered with KRASG12V-RAF interactions. The compound yielded a median EC50 of 2.1 nM and a median maximum inhibition of 93%, together with 26-fold preferential activity over wild-type K/N/HRAS [1].
The ability of RMC-5127 to suppress MAPK signaling was further examined in CAPAN-1 cells (KRASG12V mutant). Over a concentration range of 10⁻¹² M to 10⁻⁶ M, the compound inhibited pERK with an IC50 of 0.6 nM, indicating potent pathway blockade [1]. In a broad panel of KRASG12V-mutant human cancer cells, RMC-5127 consistently suppressed RAS pathway signaling, restrained proliferative capacity, and promoted apoptotic cell death. A median maximum proliferation inhibition of 93% was achieved across these lines. In contrast, only submaximal inhibition was observed in cancer cells expressing wild-type K/N/HRAS [1]. In vitro studies demonstrate that RMC-5127 potently inhibits multiple human KRAS G12V-addicted cancer cell lines. By forming the tri-complex, the drug sterically blocks RAS binding to downstream effector proteins, leading to rapid extinction of KRAS G12V(ON) signaling. Specifically, RMC-5127 suppresses ERK phosphorylation, inhibits cell proliferation, and induces apoptosis in KRAS G12V mutant cancer cells. Selectivity assays show that RMC-5127 exhibits high selectivity for KRAS G12V mutant cancer cells, while only causing submaximal inhibition in K/N/HRAS wild-type cancer cell lines. |
| ln Vivo |
When administered orally once daily at doses ranging from 3 to 200 mg/kg for up to 40 days, RMC-5127 elicited dose-dependent and robust antitumor activity in subcutaneous NCI-H441 KRASG12V/WT NSCLC xenografts. Notably, complete or near-complete tumor regression was achieved at the two highest dose levels—100 mg/kg and 200 mg/kg once daily [1].
Following a single oral dose (3–200 mg/kg), RMC-5127 exhibited dose-proportional exposure in both systemic circulation and tumor tissue. Pharmacodynamic assessment revealed that inhibition of the MAPK pathway, quantified by suppression of DUSP6 mRNA, yielded an EC50 of 157 nM derived from the PK/PD relationship curve [1]. In naive BALB/c mice receiving oral RMC-5127 at 100 mg/kg once daily for 7 consecutive days, the compound achieved readily detectable concentrations in brain parenchyma. At 4 hours following the final dose, the brain-to-blood concentration ratio was determined to be 0.14 [1]. When evaluated in an intracranial NCI-H441-Luc KRASG12V/WT NSCLC xenograft model, once-daily oral administration of RMC-5127 at 100–200 mg/kg for up to 70 days produced sustained antitumor responses. Profound tumor regression was observed specifically at the 200 mg/kg daily dose [1]. In preclinical animal models, RMC-5127 monotherapy induces tumor regressions across multiple subcutaneous xenograft models of KRAS G12V-mutant cancers, including non-small cell lung cancer, pancreatic cancer, and colorectal cancer, and is well-tolerated. Importantly, the compound is brain-penetrant, with dose-dependent exposure observed in the whole brain of naïve mice. In intracranial KRAS G12V mutant tumor xenograft models, RMC-5127 demonstrates profound and durable anti-tumor activity at well-tolerated doses, with intracranial tumor exposure comparable to that in subcutaneous tumors. Furthermore, in syngeneic mouse models, RMC-5127 treatment increases intratumoral T cell infiltration, upregulates MHC-I expression, and synergizes with anti-PD-1 therapy to achieve 100% durable complete regressions. |
| Animal Protocol |
Animal Model: Immunodeficient mice (n=3 per time point)[1]
Dosage: 3 mg/kg; 10 mg/kg; 30 mg/kg; 100 mg/kg; 200 mg/kg Administration: p.o.; single dose Result: Dose-dependent exposure was observed in both blood and tumor tissue, and compound elimination was slower in tumors compared with blood.Dose-dependent inhibition of DUSP6 mRNA expression in tumors was induced, with an EC50 of 157 nM derived from the PK/PD relationship curve. Animal Model: BALB/c mice (naive, n=3 per time point)[1] Dosage: 100 mg/kg Administration: p.o.; once daily; 7 consecutive days Result: Total brain concentration reached 568 nM at 4 hours after the last dose, with a brain-to-blood concentration ratio of 0.14.Measurable brain exposure was maintained at 24 hours post-last dose, with concentration comparable to that observed at 4 hours in tumor-bearing mice following a single 100 mg/kg oral administration. |
| ADME/Pharmacokinetics |
RMC-5127 is orally active with favorable bioavailability. Pharmacokinetic studies reveal dose-dependent whole-brain exposure in naïve mice, indicating effective blood-brain barrier penetration—a critical feature for treating advanced cancer patients with brain metastases. The molecular weight is 1062.33, with the molecular formula C57H75N9O9S. RMC-5127 has entered clinical development, with an ongoing Phase 1/1b trial in patients with advanced KRAS G12V-mutant solid tumors to evaluate safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity.
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| Toxicity/Toxicokinetics |
In preclinical studies, RMC-5127 demonstrates a favorable tolerability profile in animal models. No significant toxicities have been observed within the effective therapeutic dose range across various xenograft models. According to the safety data sheet provided by suppliers, the compound is for research use only and not for human use. The ongoing Phase 1 clinical trial will systematically assess its safety, dose-limiting toxicities, and adverse event profile in humans. As RMC-5127 remains in clinical development, the complete safety profile requires further investigation.
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| References |
[1]. RMC-5127, a first-in-class, orally bioavailable mutant-selective RASG12V(ON) inhibitor is central nervous system (CNS)-penetrant and demonstrates anti-tumor activity in a preclinical intracranial xenograft model. Cancer Res (2024) 84 (6_Supplement): 3340.
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| Molecular Formula |
C57H75N9O9S
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|---|---|
| Molecular Weight |
1062.33
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| CAS # |
3082166-76-2
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| Appearance |
White to off-white solid
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| SMILES |
[H][C@@]12C(=O)OCC(C)(C)CC3C4=CC(=CC=C4N(C=3C3C=C(N4CCN(C5CC5)CC4)C=NC=3[C@@H](OC)C)CCOC3CCOCC3)C3=CSC(=N3)[C@@H](N3CC4(COC4)C3)[C@H](NC([C@@H]3[C@@H](C)CO3)=O)C(=O)N(C3CC1C3)N2
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| Synonyms |
RMC-5127; RMC5127; 3056146-38-1; (2S,3S)-N-((64S,3S,4S)-12-(5-(4-Cyclopropylpiperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-11-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3-methyloxetane-2-carboxamide
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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 : ~100 mg/mL (~94.13 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 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 Saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (2.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 900 μL Corn Oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.9413 mL | 4.7066 mL | 9.4133 mL | |
| 5 mM | 0.1883 mL | 0.9413 mL | 1.8827 mL | |
| 10 mM | 0.0941 mL | 0.4707 mL | 0.9413 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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