| Chemical Properties | Back Directory | [density ]
1.24±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted) | [form ]
Solid | [pka]
13.44±0.40(Predicted) | [color ]
White to off-white | [InChIKey]
VYZILERTWJIGRC-UHFFFAOYSA-N | [SMILES]
C(N1C2=CC=C3C4=CC=CC(CC(C(N5CCCC(N5)C(OCC(CC(C2=C3)=C1C1C=CC=NC=1C(C)OC)(C)C)=O)=O)NC(=O)C(N1CCC2(CCN(C2)C(=O)C#CC(C)(C)N(C)C)C1=O)C(C)C)=C4)C |
| Hazard Information | Back Directory | [Uses]
RMC-4998 is an orally active inhibitor targeting the active or GTP-bound state of the KRASG12C mutant. RMC-4998 can form a ternary complex with intracellular CYPA and the activated KRASG12C mutant, with an IC50 value of 28 nM. RMC-4998 can inhibit ERK signaling in KRASG12C mutant cancer cells and induce apoptosis. RMC-4998 can be used for tumor research[1][2]. | [in vivo]
RMC-4998 (10-200 mg/kg; once daily; 28 days; p.o.) inhibits ERK phosphorylation in tumors and exhibits anti-tumor activity in mice carrying NCI-H358 xenografts[1].
RMC-4998 (80 mg/kg; once daily; 4 weeks; p.o.) can promote tumor regression in non-small cell lung cancer mice and has anti-tumor activity[2].
RMC-4998 (100 mg/kg; once daily; p.o.) induces tumor regression and inhibits ERK phosphorylation expression in sotorasib-R LU65 xenograft mice[3]. | Animal Model: | Mice model bearing H358 CDX tumors[1]. | | Dosage: | 10-200 mg/kg | | Administration: | Oral gavage (p.o.); once daily; 28 days | | Result: | Inhibited ERK phosphorylation in tumors for about 24 hours and induced cell apoptosis, leading to tumor regression. |
| Animal Model: | The cell-line derived H2122 KRASG12C lung adenocarcinoma xenograft model (CDX)[2]. | | Dosage: | 80 mg/kg | | Administration: | Oral gavage (p.o.); once daily; 4 weeks | | Result: | Inhibited tumor growth for 30-35 days. |
| Animal Model: | Sotorasib-R LU65 mice xenograft model[3]. | | Dosage: | 100 mg/kg | | Administration: | Oral gavage (p.o.); once dailys | | Result: | Reduced tumor volume and lowered the expression of pERK protein in the tumor. |
| [References]
[1] Schulze CJ, et al. Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS. Science. 2023 Aug 18;381(6659):794-799. DOI:10.1126/science.adg9652
[2] Kitai H,et al. Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer. Nat Commun. 2024 Jul 19;15(1):6076. DOI:10.1038/s41467-024-50063-z
[3] Solanki H S, et al. RTK signaling and WT RAS activity as vulnerabilities in tumors with acquired resistance to GDP-state selective KRASG12C inhibitors in preclinical models[J]. Cancer Research, 2024, 84(6_Supplement): 1924-1924. |
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