RMC-7977

A wild-type and mutant Ras protein-protein interaction inhibitor, inhibits the interaction between wild-type K-Ras and seven activating mutation-containing K-Ras variants and C-RAF (EC50s = 5.06-34.5 nM) and the same K-Ras variants and cyclophilin A (EC50s = 1.27-9.12 nM) in BRET assays using U2OS cells expressing the human proteins, inhibits the protein-protein interactions between wild-type N-Ras, N-RasQ61K, N-RasQ61L, and N-RasQ61R and B-RAF (EC50s = 57.7, 53.9, 145, and 181 nM, respectively, in TR-FRET assays) and wild-type H-Ras and H-RasG13R and B-RAF (EC50s = 59.9 and 23.7 nM, respectively, in TR-FRET assays), has antiproliferative activity against a panel of 183 K-Ras-dependent cancer cell lines (median EC50 = 2.4 nM), reduces the proliferation of adagrasib-resistant NCI H358 cells at 10 nM, reduces tumor volumes in SW620 colon, HPAC pancreatic, and NCI H441 lung cancer mouse xenograft models at 10 mg/kg per day. Formulation: A solid. InChI: InChI=1S/C47H60N8O6S/c1-6-54-39-12-9-28-18-31(39)33(43(54)32-19-30(22-48-42(32)27(2)59-5)53-16-14-52(15-17-53)29-10-11-29)21-47(3,4)26-61-46(58)36-8-7-13-55(51-36)45(57)37(20-40-49-38(28)25-62-40)50-44(56)41-34-23-60-24-35(34)41/h9,12,18-19,22,25,27,29,34-37,41,51H,6-8,10-11,13-17,20-21,23-24,26H2,1-5H3,(H,50,56)/t27-,34-,35+,36-,37-,41+/m0/s1. InChIKey: NBLZKEHVVJSAAY-VLXWOFRQSA-N. SMILES: O=C([C@H](CCC1)NN1C([C@H](CC2=NC3=CS2)NC([C@H]4[C@H]5[C@@H]4COC5)=O)=O)OCC(C)(C)CC6=[C@@]([C@@]7=C([C@H](C)OC)N=CC(N8CCN(C9CC9)CC8)=C7)N(CC)C%10=C6C=C3C=C%10