Abstract 6060: Discovery of potent SHP2 protein degraders with strong anti-tumor activities in KRAS mutant cancers

Abstract

Abstract Background: SHP2 plays a pivotal role in modulating the RTK/RAS/MAPK signaling pathway, which is frequently dysregulated in various cancers. Multiple allosteric SHP2 inhibitors have been under active development for the treatment of RTK/RAS/MAPK-dependent cancers, while certain limitations have come to light, such as their inability to target the active form of SHP2 and narrow therapeutic index necessitating intermittent dosing to mitigate toxicity. To overcome these challenges, we have discovered SHP2 protein degraders as next generation SHP2 targeting agents. Here, we present compelling profiles of our SHP2 degraders. Methods: We employed a variety of cancer cell lines harboring mutations in RTK, KRAS, or SHP2 for assessing in vitro activity of SHP2 degraders. For in vivo assessment of pharmacological profile, we utilized an NCI-H358 KRAS G12C mutant NSCLC xenograft. SHP2 protein levels in cell lysates and tumors were analyzed to assess SHP2 degradation efficiency. Simultaneously, ERK phosphorylation and DUSP6 mRNA levels were analyzed to evaluate downstream effects. Immunoprecipitation assays were used to assess the impact on SHP2's scaffolding roles. Results: A series of SHP2 degraders have been identified, demonstrating highly efficient SHP2 degradation activity with DC50 values in subnanomolar ranges. Robust inhibition of ERK phosphorylation, followed by remarkable anti-cancer effects in multiple KRAS mutant cancer cell lines were observed. Interestingly, in vitro cell growth inhibition by SHP2 degraders are 10 times more potent than SHP2 inhibitors currently under clinical development. Further characterization reveals several advantages of SHP2 degraders compared to SHP2 inhibitors. First, we observed a more efficient disruption of SHP2 scaffolding function, such as the formation of the SHP2-GRB2-GAB1 complex. Second, we detected effective degradation of activating mutants of SHP2, such as E76K and T507K, which are typically not targeted by SHP2 inhibitors. Experiments using a KRAS mutant CDX model demonstrate compelling in vivo profiles. A single administration of lead compounds resulted in Dmax values exceeding 95% in tumors, accompanied by the significant reduction of downstream signaling markers, such as p-ERK and DUSP6 mRNA. Notably, the reduced levels of SHP2 and downstream markers persist for several days. This suggests that utilizing intermittent dosing could be a viable approach with SHP2 degraders. Once-weekly intravenous administration achieved strong tumor growth inhibition without causing significant body weight loss. Conclusion: We have successfully discovered novel SHP2 degraders exhibiting remarkable activities. We demonstrate that SHP2 degraders have potential to overcome the limitations associated with allosteric SHP2 inhibitors and provide a promising therapeutic option for RTK/RAS/MAPK-dependent cancer patients. Citation Format: So Hyun Kim, Jihye Lee, Jiyoung Song, Geon-Tae Park, Jieun Jung, Jungtae Na, Dong Ho Lee, Soohyun Lee, Ji Youn Park, Jiyoung Kim, Onnuri Bae, Jeonghwa Han, Ju Young Kang, Mijin Moon, Yongje Shin, Je Ho Ryu, Song Hee Lee, Sook-Kyung Park. Discovery of potent SHP2 protein degraders with strong anti-tumor activities in KRAS mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6060.