Abstract LB194: Revolutionizing cancer treatment with the first SHP2 PROTAC

Abstract SHP2 is a mediator in tumor-related signaling pathway, a suppressor of PD-1, associated with solid tumors and leukemias. SHP2 is recognized as a driver in myeloid leukemia. Inhibition of SHP2 has potential to reverse progression of myeloid leukemia, rather than eradicating differentiated leukemic cells. However, SHP2's bifunctional roles-encompassing both phosphatase-dependent and -independent activities-pose challenges for therapeutic targeting. SHP2 inhibitors, like JAB3312, is limited to inhibiting phosphatase activity and evaluated in combination regimens rather than as standalone therapies. To address limitations, we developed a PROTACs with a novel, high-affinity as warhead. This strategy enables complete degradation of SHP2, we developed a novel SHP2 degrader TDS0593, exhibited superior preclinical performance. In vitro, TDS0593 achieved dose-dependent SHP2 degradation, with a Dmax of 91.7% and a DC50 of 1.145 nM in MV411 leukemia cells. Mechanistic studies confirmed TRD209 acts via ubiquitin-proteasome pathway, as validated by TAK-243 and MG132 blockade assays. In vivo, TDS0593 demonstrated potent antitumor efficacy. In MV411 xenograft models, at 2.5 mg/kg (QD) achieved >90% TGI, a 5 mg/kg (QD) dose resulted in complete TGI. In order to established mouse model, leukemia HSC from donor mice with CD45.2 cells has been transplanted into CD45.1 mice. In murine models, administration of TDS0593 resulted in a significant reduction in proportion of myeloid cells both in PB and BM. The number of myeloid stem and progenitor cells in the BM approached normal levels. TDS0593 corrects the aberrant differentiation pathway of hematopoietic stem cells to a certain extent, highlighting its potential as an etiological treatment for myeloid leukemia. Notably, TRD209 showed greater potency in solid tumor PDX, with a 0.5 mg/kg (QD) dose achieving >99% TGI. Immunohistochemical analysis confirmed suppression of p-ERK1/2 expression in tumors either. TDS0593 represents a first-in-class SHP2 degrader with potential to overcome the limitations of current inhibitors by targeting both phosphatase-dependent and -independent activities. TDS0593 offer a novel strategy for the treatment of myeloid leukemia by correcting aberrant myeloid-biased differentiation of HSC/HSPC. This innovative approach aims to rectify the underlying dysregulation in hematopoietic differentiation processes, achieving efficacy in myeloid leukemia. Citation Format: Junrong Liu, Liying Zhou, Xiaobo Li, Wenming Li. Revolutionizing cancer treatment with the first SHP2 PROTAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB194.