Abstract 387: Preclinical biological screening and evaluation of KRAS molecular glues

Abstract The KRAS protein is a signal transduction molecule associated with various types of cancer. Due to its high mutation rate and key role in tumor development, KRAS has become an important target for anti-cancer drug development. Activating mutations in KRAS, such as KRASG12C, are prevalent in about one-third of all human cancers and significantly contribute to tumor initiation, progression, and resistance to therapy. In recent years, with the continuous deepening of research related to KRAS, a new therapeutic strategy targeting the KRAS protein has been discovered, known as KRAS molecular glue. KRAS molecular glue specifically binds to particular mutation sites on the KRAS protein, such as the G12C mutation, thereby preventing its interaction with downstream signaling molecules and inhibiting the proliferation and survival of tumor cells. In this context, we have developed a comprehensive screening and evaluation platform for KRAS molecular glue, covering studies from in vitro to in vivo. The platform includes a series of assays at both the biochemical and cellular levels. It utilizes biochemical and biophysical methods for the screening of POI binders, detection of KRAS(ON)/CypA/cRAF binary complexes, and KRAS(ON)/CypA ternary complexes, among others. Cell-based functional assays such as 3D cell proliferation and detection of ERK phosphorylation, a marker related to signaling pathways, are also included. Additionally, we offer p-ERK panel and 2D/3D cell panel including pan KRAS cell panel, KRAS G12D cell panel, KRAS G12C cell panel, KRAS G12V cell panel, pan NRAS cell panel and pan HRAS cell panel tests for KRAS molecular glue, and we can also supply KRAS G12C mutation-resistant cell lines for related testing. Of course, it also includes the efficacy assessment of the CDX model in vivo. 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, Lili Chai, Xian Wu, Tao Li, Xiaojian Wang, Tj (Tiejun) Bing. Preclinical biological screening and evaluation of KRAS molecular glues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 387.