RMC-7977
RMC-7977 Basic information
- Product Name:
- RMC-7977
- Synonyms:
-
- RMC-7977
- (1α,5α,6α)-N-[(2R,14S,18S)-2-[5-(4-Cyclopropyl-1-piperazinyl)-2-[(1S)-1-methoxyethyl]-3-pyridinyl]-1-ethyl-18,19,20,21-tetrahydro-25,25-dimethyl-15,22-dioxo-17H-5,3-([4,2]-endo-thiazolopropano[1,3]-endo-pyridazinomethanoxypropano)-1H-indol-14-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide
- 3-Oxabicyclo[3.1.0]hexane-6-carboxamide, N-[(2R,14S,18S)-2-[5-(4-cyclopropyl-1-piperazinyl)-2-[(1S)-1-methoxyethyl]-3-pyridinyl]-1-ethyl-18,19,20,21-tetrahydro-25,25-dimethyl-15,22-dioxo-17H-5,3-([4,2]-endo-thiazolopropano[1,3]-endo-pyridazinomethanoxypropano)-1H-indol-14-yl]-, (1α,5α,6α)-
- CAS:
- 2765082-12-8
- MF:
- C47H60N8O6S
- MW:
- 865.1
- Mol File:
- 2765082-12-8.mol
RMC-7977 Chemical Properties
- Density
- 1.46±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)
- solubility
- DMSO: Soluble: =10 mg/ml
Ethanol: Soluble: =10 mg/ml - pka
- 13.85±0.40(Predicted)
- form
- Solid
- color
- White to light yellow
- InChIKey
- NBLZKEHVVJSAAY-UHFFFAOYSA-N
- SMILES
- C(N1C2=CC=C3C4=CSC(CC(C(N5CCCC(N5)C(OCC(CC(C2=C3)=C1C1C=C(N2CCN(C3CC3)CC2)C=NC=1C(C)OC)(C)C)=O)=O)NC(C1C2COCC12)=O)=N4)C
RMC-7977 Usage And Synthesis
Uses
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].
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].
| 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. |
IC 50
c-Raf; KRAS(G12C); H-Ras; NRAS rG4
References
[1] Singh M, et al. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Research Square; 2023. DOI:10.1038/s41586-024-07205-6
[2] Popescu B, et al. RAS MULTI (ON) inhibitor RMC-7977 targets oncogenic RAS mutations and overcomes RAS/MAPK-mediated resistance to FLT3 inhibitors in AML models[J]. Blood, 2023, 142: 2793.
[3] Wasko UN, et al. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature. 2024 May;629(8013):927-936. DOI:10.1038/s41586-024-07379-z
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