ChemicalBook Product Catalog Biochemical Engineering Inhibitors RMC6236

RMC6236

Product NameRMC6236
CAS2765081-21-6
MFC44H58N8O5S
MW811.05
EINECS
MOL File2765081-21-6.mol

Chemical Properties

Density	1.37±0.1 g/cm3(Predicted)
solubility	DMSO: Sparingly soluble: 1-10 mg/ml Ethanol: Sparingly soluble: 1-10 mg/ml
pka	14.56±0.40(Predicted)
form	Solid
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

Usage And Synthesis

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].

Synthesis

The synthesis of RMC-6236 starts from 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine and benzylpiperazine-1-carboxylate, involving palladium-catalyzed couplings, borylation, Suzuki couplings to introduce indole and thiazole moieties, followed by macrocyclization and deprotection steps, and final amidation with (1S,2S)-2-methylcyclopropane-1-carboxylic acid. Key steps include: borylation of T1 to give T2 (crude); Suzuki coupling giving T3 in 48.1% yield; separation of two atropisomers from T5 (A: 36%, B: 34%); borylation of T6 in 76.0% yield; coupling to T7 in 50.9% yield; hydrolysis to T8 in 84.5% yield; macrocyclization to T9 in 54.8% yield; Cbz removal to T10 in 90.4% yield; methylation to T11 in 58.01% yield; final product RMC-6236 in 22.0% yield and 96.4% purity [4].
synthesis of RMC6236

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 KRAS^G12C-mutant NCI-H2122 non-small cell lung cancer and KRAS^G12D-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
[4] Jiang, J., Jiang, L., Maldonato, B. J., et al. (2024). Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discovery, 14(6), 994–1017. https://doi.org/10.1158/2159-8290.cd-24-0027

RMC6236 Supplier

RMC6236 manufacturers

Related Product Information

Send Inquriy