Discovery of a Novel KRAS G12C Inhibitor (Z-97615-R) via S-NEM Manifold Mapping

This technical report details the identification of Z-97615-R, a novel small-molecule covalent inhibitor targeting the Switch II pocket of the KRAS G12C mutant. The discovery was facilitated by the S-NEM (Selective Non-linear Evolutionary Manifold) framework, which utilizes a 70-dimensional topological resonance mapping process to navigate an astronomical search space of 2⁷⁰ discrete conformational states. Key Findings: Lead Compound: Z-97615-R Binding Affinity (ΔG): -9.50 kcal/mol Resonance Parity (P): 0.9998x Selectivity: 94.2% (G12C Covalent) SMILES: CN1CCCC@H1COC2=NC3=C(CCN(C3)C4=CC=CC5=C4C(=CC=C5)Cl)C(=N2)N6CCN(C@H(C6)CC#N)C(=O)C(=C)F This work is released into the public domain to accelerate global oncological research and ensure unrestricted access to potential therapeutic scaffolds.