RMC-6291   Click here for help

GtoPdb Ligand ID: 12622

Compound class: Synthetic organic
Comment: RMC-6291 is a KRASG12C(ON) inhibitor [1], that inhibits active, GTP-bound RAS. It is designed to bind to the immunophilin cyclophilin A (PPIA) via a moiety containing a minimal cyclophilin A-binding motif of the naturally ocurring immunosuppressive (cyclophilin inhibiting) polyketide Sanglifehrin A. It also contains a cysteine-reactive warhead to mediate covalent tethering to KRAS. The resulting RMC-6291:cyclophilin A structure has high affinity for the active state of KRASG12C and forms a RMC-6291:cyclophilin A:KRASG12C tri-complex that causes steric hindrance for RAS effector binding thus blocking oncogenic signalling. The chemical structure of RMC-6291 was disclosed during the 'First Disclosures of New Drug Candidates' session at the April 2023 meeting of the AACR in Orlando. RMC-6291 was developed for anti-tumour potential.
2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 17
Hydrogen bond donors 2
Rotatable bonds 13
Topological polar surface area 168.9
Molecular weight 1012.26
XLogP 5.49
No. Lipinski's rules broken 3
SMILES / InChI / InChIKey
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Canonical SMILES CCN1C2=CC=C3C=C2C(=C1C4=C([C@H](C)OC)N=CC=C4)CC(C)(C)COC(=O)[C@@H]5CCCN(C(=O)[C@@H](C[C@H]6CN3CCO6)NC(=O)[C@H](C(C)C)N(C)C(=O)C7(CCN(CC7)C(=O)C#CC(C)(C)N(C)C)F)N5
Isomeric SMILES CCN1C2=C3C=C(C=C2)N4CCO[C@H](C4)C[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)C5(F)CCN(CC5)C(=O)C#CC(C)(C)N(C)C)C(=O)N6CCC[C@H](N6)C(=O)OCC(C)(C)CC3=C1C7=C(N=CC=C7)[C@H](C)OC
InChI InChI=1S/C55H78FN9O8/c1-13-64-44-19-18-37-30-40(44)41(48(64)39-16-14-24-57-46(39)36(4)71-12)32-53(5,6)34-73-51(69)42-17-15-25-65(59-42)50(68)43(31-38-33-63(37)28-29-72-38)58-49(67)47(35(2)3)61(11)52(70)55(56)22-26-62(27-23-55)45(66)20-21-54(7,8)60(9)10/h14,16,18-19,24,30,35-36,38,42-43,47,59H,13,15,17,22-23,25-29,31-34H2,1-12H3,(H,58,67)/t36-,38-,42-,43+,47-/m0/s1
InChI Key HJNFYLSFWYRSHS-JVFAQLKDSA-N