Discovery of Novel SHP2 ATTEC Degraders against Pancreatic Ductal Adenocarcinoma Harboring KRAS(G12D) Mutations

Aberrant expression of the phosphatase SHP2 is implicated in numerous cancers, including KRAS G12D mutation driven PDAC. Although several SHP2 inhibitors have been reported, specific inhibitors with potent efficacy are not yet available. Given the elevated autophagy in PDAC, herein, we first designed novel SHP2 degraders through autophagosome-tethering compound strategy. Among them, the preferred <b>11n</b> formed hydrogen bonds with Arg 111 and Glu 250 residues of SHP2 to enhance interactions between SHP2 and LC3. <b>11n</b> also possessed great efficacy and selectivity against KRAS G12D mutant cancer cells versus the wild type. Moreover, the degradation caused by <b>11n</b> manipulated the signaling pathways associated with cell apoptosis, metastasis, and invasion to inhibit the tumor growth both in <i>vitro</i> and in <i>vivo</i>. These findings not only generated a useful tool for exploring the potential of targeting SHP2 degradation but also offered promising candidates to develop novel drugs based on the autophagy mechanism.