Abstract 1661: Discovery of an SHP2 degrader with potent anti-cancer activity as a monotherapy and exceptional combination effects in KRAS mutant cancers

Abstract Background: SHP2 is a key regulator of the RTK/RAS/MAPK signaling pathway, which is often disrupted in various cancers. Numerous allosteric SHP2 inhibitors are being actively developed to treat cancers driven by this pathway. However, these inhibitors face certain challenges, including their inability to target the active form of SHP2 and a narrow therapeutic window that requires intermittent dosing to manage toxicity. To address these limitations, we have developed SHP2 protein degraders as next-generation therapeutic agents targeting SHP2. In this study, we present the compelling characteristics of our SHP2 degraders. Methods: For inhibitor combination assay, we did clonogenic assay in NCI-H358 KRAS G12C mutant NSCLC and 3D proliferation in various cell lines. For in vivo assessment of pharmacological profile, we utilized an NCI-H358 xenograft. SHP2 protein levels in cell lysates and tumors were analyzed to assess SHP2 degradation efficiency and DUSP6 mRNA levels were analyzed to evaluate downstream effects. For selectivity analysis, we analyzed phosphatase panel profiling and proteomics. Results: Our compounds showed superior degradation activity achieving sub-nanomolar DC50 levels and significant cell growth inhibition exhibiting single digit nanomolar IC50 levels in NCI-H358 NSCLC (non-small cell lung cancer). In clonogenic and 3D cell proliferation assay, compound 5 showed significant growth inhibition with various inhibitors such as EGFR, MEK, ALK, RAF and KRAS G12C inhibitors. Phosphatase panel profiling and proteomics demonstrated compound 5 degraded SHP2 selectively. In particular, the superior anti-cancer effects of combination treatments with other drugs were confirmed across various cancer cell lines. In vivo experiments using a KRAS mutant CDX model revealed compelling in vivo profiles. Once-weekly intravenous administration achieved strong tumor growth inhibition without inducing the hematological and liver toxicities that were issues in the clinical studies of SHP2 inhibitors. Conclusion: We have successfully identified new SHP2 degraders with exceptional activity. Our findings demonstrate that, by leveraging the characteristics of these degraders as a strategy to overcome toxicity, they have the potential to address the limitations of allosteric SHP2 inhibitors, offering a promising therapeutic approach for patients with RTK/RAS/MAPK-dependent cancers. Citation Format: Soohyun Lee, Jiyoung Kim, Ji Youn Park, Beomseon Suh, Han Wool Kim, So Hyuk Kim, Hyun-Hwi Kim, Onnuri Bae, Jeonghwa Han, Ju Young Kang, Jihye Lee, Je Ho Ryu, Song Hee Lee. Discovery of an SHP2 degrader with potent anti-cancer activity as a monotherapy and exceptional combination effects in KRAS mutant cancers [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 1661.