Description

RMC-6236 is a first-in-class, potent, oral RAS-selective tri-complex, RAS(MULTI)(ON) inhibitor with an attractive preclinical profile and is designed to treat cancers caused by multiple RAS variants for which no targeted treatment is currently available. Upon oral administration, RAS inhibitor RMC-6236 binds to an intracellular chaperone protein, cyclophilin A (CypA). The resulting inhibitory binary complex binds to active, GTP-bound RAS to form a tri-complex. This tri-complex inhibits RAS-dependent signaling and inhibits the proliferation of tumor cells in which RAS is overexpressed and/or mutated. RAS plays an important role in cell signaling, division and differentiation. Mutations of RAS may induce constitutive signal transduction leading to tumor cell growth, proliferation, invasion, and metastasis.

IC50 Confirmation:
After testing both mouse and human PDAC, IC50 values for RMC-6236 fall within the range of 20-40nM.

SUIT2 Cell Line Activity:
activity test using the SUIT2 cell line, IC50, 2.02nm

Technical Data

Product Name	RMC-6236
Chemical Formula	C44H58N8O5S
Molecular Weight	811.06
CAS#	2765081-21-6
Appearance	Solid powder
Purity	> 99% by HPLC
Solubility	Soluble in DMSO
Storage	Room temperature for months, or -20ºC for 3 years
Targets	RAS(ON); RAS(MULTI)(ON)
Synonym	RMC-6236; RMC6236; RMC 6236, KRAS, RAS

Chemical Name/IUPAC:(1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide

SMILES Code: CC(COC([C@H]1NN(C([C@H](CC2=NC3=CS2)NC([C@H]4C[C@@H]4C)=O)=O)CCC1)=O)(C)CC5=[C@@](N(CC)C6=C5C=C3C=C6)[C@@]7=C([C@H](C)OC)N=CC(N8CCN(C)CC8)=C7

For Research Use Only.

References

[1] Trends Cancer. 2023 Jan;9(1):42-54. doi: 10.1016/j.trecan.2022.10.001. Epub 2022 Oct 28. Precision oncology provides opportunities for targeting KRAS-inhibitor resistance. Martin Sattler 1, Atish Mohanty 2, Prakash Kulkarni 2, Ravi Salgia 3

[2] Mullard A. The KRAS crowd targets its next cancer mutations. Nat Rev Drug Discov. 2023 Jan 23. doi: 10.1038/d41573-023-00015-x. Epub ahead of print.

[3] Wang X, Marx MA. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J Med Chem. 2022 Feb 24;65(4):3123-3133. doi: 10.1021/acs.jmedchem.1c01688. Epub 2021 Dec 10.

Document

MSDS-RMC-6236