2. GPCR/G Protein MAPK/ERK Pathway Stem Cell/Wnt Epigenetics PI3K/Akt/mTOR Apoptosis Cell Cycle/DNA Damage
  3. Ras ERK Raf Ribosomal S6 Kinase (RSK) AMPK Apoptosis PARP
  4. RMC-7977

RMC-7977 is an orally active triple-complex RAS inhibitor that can simultaneously bind to cyclophilin A (CYPA) (Kd = 195 nM) and KRAS (G12V) (Kd = 292 μM). It exhibits broad-spectrum inhibitory activity against KRAS, NRAS, and HRAS proteins and their various wild-type and mutant variants. RMC-7977 induces apoptosis by inhibiting the phosphorylation of ERK, CRAF, and RSK, as well as increasing PARP cleavage. This leads to tumor regression, reduces resistance in KRASG12C cancer models, and demonstrates good tolerability across various RAS cancer models.

For research use only. We do not sell to patients.

RMC-7977 Chemical Structure

RMC-7977 Chemical Structure

CAS No. : 2765082-12-8

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Solid + Solvent (Highly Recommended)
10 mM * 1 mL in DMSO
ready for reconstitution
 USD 1190 In-stock
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Based on 1 publication(s) in Google Scholar

RMC-7977 Related Antibodies

Top Publications Citing Use of Products

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K-Ras H-Ras N-Ras Ras

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ERK ERK1 ERK2 ERK5 ERK8

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BRaf c-Raf Raf

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p70S6K RSK1 RSK2 RSK3 RSK4

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NUAK1 NUAK2 AMPK AMPK α1β1γ1 AMPK α2β1γ1 AMPK α1β2γ1 AMPK α2β2γ1

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PARP PARP1 PARP2 PARP3 PARP4 TNKS1/PARP5A TNKS2/PARP5B PARP7 PARP10 PARP14 PARP15 PARP12 PARP16

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  • Purity & Documentation

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  • Customer Review

Description

RMC-7977 is an orally active triple-complex RAS inhibitor that can simultaneously bind to cyclophilin A (CYPA) (Kd = 195 nM) and KRAS (G12V) (Kd = 292 μM). It exhibits broad-spectrum inhibitory activity against KRAS, NRAS, and HRAS proteins and their various wild-type and mutant variants. RMC-7977 induces apoptosis by inhibiting the phosphorylation of ERK, CRAF, and RSK, as well as increasing PARP cleavage. This leads to tumor regression, reduces resistance in KRASG12C cancer models, and demonstrates good tolerability across various RAS cancer models[1][2][3].

IC50 & Target

c-Raf

 

KRAS(G12C)

 

H-Ras

 

NRAS rG4

 

In Vitro

RMC-7977 (3-300 nM, 24 h) exhibits inhibitory activity on the KRAS signaling pathway in mouse embryonic fibroblasts (MEFs, Ras gene-deficient, restored by introducing wild-type or mutant KRAS genes to express KRAS protein)[1].
RMC-7977 (0.1-10 nM, 48 h) inhibits proliferation and downstream signaling (i.e., decreases pERK levels) in RAS-dependent cancer cells (i.e., cancer cells with RAS pathway activation due to mutations in KRAS, NRAS, or EGFR) in a concentration-dependent manner[1].
RMC-7977 (1-100 nM, 48 h) can induce apoptosis in KRASG12V and KRASG12C cells by inhibiting the phosphorylation of RAF, ERK, and RSK, and increasing PARP cleavage[1].
RMC-7977 (5-33 nM, 96 h) inhibits the proliferation of acute myeloid leukemia (AML) cell lines driven by FLT3-ITD (Molm-14, MV4-11), KIT (Kasumi-1, SKNO-1), and RAS mutations (NRAS - OCIAML-3, HL-60, KRAS - NOMO-1) with an IC50 value in the range of 5-33 nM and also inhibits MAPK pathway signaling[2].

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

RMC-7977 Related Antibodies

Cell Viability Assay[1]

Cell Line: KRASG12X mutant cell lines; KRAS wild-type cell lines, NRAS and HRAS mutant cell lines; Human cancer cell lines with mutations or fusions of EGFR, ERBB3, FGFR1, FGFR2, FGFR3, ROS1, RET, NTRK1, and ALK; Wild-type MET gene amplification cell line
Concentration: 0-1 μM
Incubation Time: 4 h
Result: Exhibited strong inhibitory effects on KRASG12X mutant cell lines, with a median EC50 of 2.40 nM.
Exhibited inhibitory effects on KRAS wild-type genotypes, including NRAS and HRAS mutant cell lines (median EC50 = 6.76 nM), as well as cell lines with mutations or fusions of EGFR, ERBB3, FGFR1, FGFR2, FGFR3, ROS1, RET, NTRK1, and ALK (median EC50 = 6.14 nM).
Exhibited inhibitory effects on cell lines with wild-type MET gene amplification (median EC50 = 6.61 nM).

Western Blot Analysis[1]

Cell Line: RAS-less mouse embryonic fibroblasts (MEFs) (introduced with exogenous wild-type or mutant KRAS genes or BRAF(V600E))
Concentration: 3, 10, 30, 100, 300 nM
Incubation Time: 24 h
Result: Suppressed pERK in all KRAS-expressing cells, but not in BRAF(V600E)-expressing RAS-less MEFs.
In Vivo

Compared to using RMC-4550 (HY-116009, a SHP2 inhibitor) and Coibmetinib (a MEK inhibitor) to inhibit RAS-MAPK downstream signaling pathway activity, directly targeting active RAS with RMC-7977 (10 mg/kg, p.o., once daily for 5 consecutive days per week followed by 2 days of cessation, for a total of 28 days) demonstrates superior anti-tumor activity in xenograft KRASG12X mouse models[1].
RMC-7977 (10 mg/kg, p.o., once daily for 5 days per week followed by 2 days off, for a total of 90 days) demonstrates significant anti-tumor activity in PDAC, CRC, and NSCLC models with KRASG12X mutations and in xenograft mice models, induces durable tumor regression, and shows good tolerability in the mouse models[1].
RAS inhibition mediated by RMC-7977 (10 mg/kg, oral administration, once daily for 28 days) does not impair immune cell function in immunocompetent mice[1].
RMC-7977 (10 mg/kg, p.o., once daily for 28 days) can inhibit the adaptive resistance to KRAS(G12C) inhibitors in a PDX mice model with KRAS(G12C) mutations (derived from NSCLC tumor cells that relapsed after Sotorasib (HY-114277) treatment)[1].
RMC-7977 (10-50 mg/kg, p.o., single dose) effectively inhibits RAS-MAPK signaling in human pancreatic ductal adenocarcinoma (PDAC) xenograft mouse models (Capan-1 (KRASG12V)) and maintains high concentrations in tumor tissue[3].

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

Animal Model: Subcutaneously implanted NCI-H441 CDX model of non-small cell lung cancer xenograft tumor (NSCLC) in BALB/c mice[1]
Dosage: 10 mg/kg
Administration: Oral gavage (p.o.), single dose or once daily for 5 days, followed by a 2-day break, totally for 28 days
Result: Had an EC50 value of 130 nM for DUSP6 in the NCI-H441 non-small cell lung cancer (NSCLC) model.
Was well tolerated and resulted in 83% mean tumour regression following 28 days of treatment in the NCI-H441 model.
Was sufficient to maximally suppress tumour DUSP6 levels (91%) at 8 h at a single oral dose.
Was observed to have prolonged exposure in tumors, with overall exposure in subcutaneous tumors increasing approximately threefold compared to blood.
Animal Model: PDAC, CRC, NSCLC CDX and patient-derived xenograft (PDX) mice models (bearing KRASG12X mutations)[1]
Dosage: 10 mg/kg
Administration: Oral gavage (p.o.), once daily for 90 days
Result: Caused tumor regression in 9 out of 15 (60%) RAS-addicted cancer mouse models after 4 to 6 weeks of administration.
Had minimal effects on body weight across all models.
Exhibited anti-tumor activity and maintained cytostatic responses after extending the administration to 90 days.
Animal Model: Human Clinical-Derived Xenograft mice model of PDAC (Capan-1 (KRASG12V))[3]
Dosage: 10, 25, 50 mg/kg
Administration: Oral gavage, single dose
Result: Was exposed in Capan-1 xenograft tumors for three times longer than in the blood.
Inhibited DUSP6 levels within 24-48 hours, with an EC50 of 142 nM.
Molecular Weight

865.11

Formula

C47H60N8O6S
CAS No.
Appearance

Solid

Color

White to light yellow

SMILES

CO[C@H](C1=[C@@](C=C(N2CCN(C3CC3)CC2)C=N1)[C@@](N4CC)=C(C5=C4C=CC6=C5)CC(C)(C)COC([C@@H](N7)CCCN7C([C@@H](NC([C@@H]8[C@@H]9[C@H]8COC9)=O)CC%10=NC6=CS%10)=O)=O)C
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 : 116.67 mg/mL (134.86 mM; Need ultrasonic; 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 1.1559 mL 5.7796 mL 11.5592 mL
5 mM 0.2312 mL 1.1559 mL 2.3118 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.

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Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

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In Vivo:

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:  2% DMSO    40% PEG300    5% Tween-80    53% Saline

    Solubility: ≥ 2 mg/mL (2.31 mM); Clear solution

  • Protocol 2

    Add each solvent one by one:  2% DMSO    98% (20% SBE-β-CD in Saline)

    Solubility: 2 mg/mL (2.31 mM); Suspended solution; Need ultrasonic

In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:

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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
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Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Calculation results:
Working solution concentration: mg/mL
Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).
The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
 If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Purity & Documentation

Purity: 99.48%

COA (254 KB) HNMR (328 KB) LCMS (93 KB)

Handling Instructions (2659 KB)
References

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.

Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 1.1559 mL 5.7796 mL 11.5592 mL 28.8981 mL
5 mM 0.2312 mL 1.1559 mL 2.3118 mL 5.7796 mL
10 mM 0.1156 mL 0.5780 mL 1.1559 mL 2.8898 mL
15 mM 0.0771 mL 0.3853 mL 0.7706 mL 1.9265 mL
20 mM 0.0578 mL 0.2890 mL 0.5780 mL 1.4449 mL
25 mM 0.0462 mL 0.2312 mL 0.4624 mL 1.1559 mL
30 mM 0.0385 mL 0.1927 mL 0.3853 mL 0.9633 mL
40 mM 0.0289 mL 0.1445 mL 0.2890 mL 0.7225 mL
50 mM 0.0231 mL 0.1156 mL 0.2312 mL 0.5780 mL
60 mM 0.0193 mL 0.0963 mL 0.1927 mL 0.4816 mL
80 mM 0.0144 mL 0.0722 mL 0.1445 mL 0.3612 mL
100 mM 0.0116 mL 0.0578 mL 0.1156 mL 0.2890 mL
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  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

RMC-79772765082-12-8RMC7977RMC 7977RasERKRafRibosomal S6 Kinase (RSK)AMPKApoptosisPARPExtracellular signal regulated kinasesRaf kinasesS6KAMP-activated protein kinasepoly ADP ribose polymerasereversibletri-complexRASbroad spectrumKRASNRASHRAS variantscancerInhibitorinhibitorinhibit

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