RMC-6236

RMC-6236 is a non-covalent inhibitor of GTP-bound RAS. It binds to peptidyl-prolyl cis-trans isomerase A (PPIase A), also known as cyclophilin A (CypA, Kd = 55.3 nM) to form a binary complex that then binds to wild-type K-Ras, K-Ras(G12V), and K-Ras(G12D) (Kds = 131, 364, and 154 nM, respectively). RMC-6236 forms a trimeric complex with PPIase A and a K-Ras, H-Ras, N-Ras, or mutant Ras variant and disrupts the protein-protein interaction between these Ras variants and the B-RAF Ras-binding domain (IC50s = 28-220 nM). It induces apoptosis in 28 K-Ras(G12X) and five N-Ras(Q61X) mutant cancer cell lines when used at concentrations ranging from 1 to 100 nM. In vivo, RMC-6236 (25 mg/kg) inhibits intratumoral ERK phosphorylation and reduces tumor volume in Capan-2 and NCI H441 pancreatic ductal adenocarcinoma (PDAC) mouse xenograft models. It also reduces tumor growth in 29 non-small cell lung cancer (NSCLC), 22 PDAC, and 23 colorectal cancer K-Ras(G12X) mutant mouse xenograft models when administered at a dose of 25 mg/kg.Formal Name: (1S,2S)-N-[(2R,14S,18S)-1-ethyl-18,19,20,21-tetrahydro-2-[2-[(1S)-1-methoxyethyl]-5-(4-methyl-1-piperazinyl)-3-pyridinyl]-25,25-dimethyl-15,22-dioxo-17H-5,3-([4,2]-endo-thiazolopropano[1,3]-endo-pyridazinomethanoxypropano)-1H-indol-14-yl]-2-methyl-cyclopropanecarboxamide. CAS Number: 2765081-21-6. Molecular Formula: C44H58N8O5S. Formula Weight: 811.1. Purity: >98%. Formulation: (Request formulation change), A solid. Solubility: DMSO: Sparingly soluble: 1-10 mg/ml, Ethanol: Sparingly soluble: 1-10 mg/ml. SMILES: O=C([C@H](CCC1)NN1C([C@H](CC2=NC3=CS2)NC([C@H]4C[C@@H]4C)=O)=O)OCC(C)(C)CC5=[C@@]([C@@]6=C([C@H](C)OC)N=CC(N7CCN(C)CC7)=C6)N(CC)C8=C5C=C3C=C8. InChi Code: InChI=1S/C44H58N8O5S/c1-8-51-37-12-11-28-19-31(37)33(40(51)32-20-29(23-45-39(32)27(3)56-7)50-16-14-49(6)15-17-50)22-44(4,5)25-57-43(55)34-10-9-13-52(48-34)42(54)35(21-38-46-36(28)24-58-38)47-41(53)30-18-26(30)2/h11-12,19-20,23-24,26-27,30,34-35,48H,8-10,13-18,21-22,25H2,1-7H3,(H,47,53)/t26-,27-,30-,34-,35-/m0/s1. InChi Key: FVICRBSEYSHKFY-JYQNNKODSA-N.