| Identification | Back Directory | [Name]
RMC6236 | [CAS]
2765081-21-6 | [Synonyms]
RMC6236
N-[21-ethyl-20-[2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.12,5.19,13.022,26]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methylcyclopropane-1-carboxamide | [Molecular Formula]
C44H58N8O5S | [MOL File]
2765081-21-6.mol | [Molecular Weight]
811.06 |
| Chemical Properties | Back Directory | [density ]
1.37±0.1 g/cm3(Predicted) | [solubility ]
DMSO: Sparingly soluble: 1-10 mg/ml
Ethanol: Sparingly soluble: 1-10 mg/ml | [form ]
Solid | [pka]
14.56±0.40(Predicted) | [color ]
White to off-white | [InChIKey]
FVICRBSEYSHKFY-UHFFFAOYSA-N | [SMILES]
C(N1C2=CC=C3C4=CSC(CC(C(=O)N5CCCC(N5)C(=O)OCC(C)(C)CC(C2=C3)=C1C1C=C(N2CCN(C)CC2)C=NC=1C(C)OC)NC(C1CC1C)=O)=N4)C |
| Hazard Information | Back Directory | [Uses]
RMC-6236 is an orally active, non-covalent RAS (ON) inhibitor. RMC-6236 disrupts the interaction of wild-type or mutant RAS proteins with the RAS binding domain of BRAF, with EC50 values ranging from 28-220 nM for wild-type KRAS, NRAS, HRAS, and multiple oncogenic RAS variants. RMC-6236 inhibits pERK. RMC-6236 has anti-tumor activity against KRAS mutant tumors[1][2][3]. | [in vivo]
RMC-6236 (3-25 mg/kg; p.o.; single dose) shows dose-dependent blood and tumor exposure in the Capan-2 xenograft tumor-bearing BALB/c nude mouse model, with tumor exposure approximately 3-7 times higher than that in blood and relatively slower elimination from tumors[1].
RMC-6236 (10-25 mg/kg; p.o.; once daily; 4 weeks) shows dose-dependent antitumor activity in a series of human tumor xenograft models harboring prevalent KRAS mutations (such as Capan-2, NCI-H441, HPAC, NCI-H358, etc.)[1].
RMC-6236 (25 mg/kg; p.o.; once daily) can arrest tumor growth when used alone in xenograft models of KRASG12C-mutant NCI-H2122 non-small cell lung cancer and KRASG12D-mutant GP2D colorectal cancer, and it can lead to significant tumor regression when combined with KO-2806[2].
| [IC 50]
KRas G12D | [References]
[1] Jiang J, et al. Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discov. 2024 Jun 3;14(6):994-1017. DOI:10.1158/2159-8290.CD-24-0027
[2] Patel H V, et al. The farnesyl transferase inhibitor KO-2806 re-sensitizes relapsing tumors to RAS inhibition. BioRxiv, 2024: 2024.12. 20.629824.
[3] Long SA, et al. Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment. Front Oncol. 2024 May 10;14:1402128. DOI:10.3389/fonc.2024.1402128 |
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