Abstract A078: Molecule Glue Profiling Unveils the Dynamics of KRAS-Induced Proximity

Abstract KRAS molecule glues inhibit KRAS activity by binding to cellular chaperone proteins (such as cyclophilin A, CYPA) to form a complex. For example, RMC6236, a pan-KRAS molecular glue, was recently found to exhibit resistance to the KRAS G12C/Y64H mutation in testing; RMC-9805, a bifunctional "molecular glue-covalent inhibitor," enhances CYPA-KRAS G12D binding and stabilizes the ternary complex; and RMC5127, a non-covalent selective molecular glue targeting KRAS G12V, all inhibit the activity of KRAS or KRAS mutations by forming CYPA/MG/KRAS ternary complexes. Research on KRAS molecular glues is continuously achieving breakthroughs. These advancements not only provide new strategies for treating KRAS-mutant cancers but also open up novel pathways for drug development against "undruggable" targets. Our integrated platform uses advanced in vitro assays to explore these KRAS MGs, including KRAS/CYPA ternary assay, KRAS(ON)/CypA/cRAF binding assay, 2D/3D cell proliferation assay, ERK phosphorylation detection, and cellular NanoRET assay for RAS-RAF disruption. It also including p-ERK panel and 2D/3D cell panel. Overall, we provide a comprehensive platform for the screening and evaluation of KRAS molecular glue, offering a scientific basis for the clinical application of KRAS molecular glue. Citation Format: Zhaoxia Yin, Xiaojian Wang, Tiejun Bing. Molecule Glue Profiling Unveils the Dynamics of KRAS-Induced Proximity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A078.