SHP2protein degrader-3 is an AUTAC protein degrader specifically targeting SHP2. It induces dose-dependent degradation of SHP2 in HeLa cells, with a DC50 of 3.22 μM, and demonstrates significant antitumor activity with an IC50 of 5.59 μM. The degradation mechanism is mediated via LC3-dependent autophagy, which can be inhibited by lysosomal inhibitors. SHP2protein degrader-3 also induces apoptosis in various tumor cell lines, including cervical cancer cells (HeLa), liver cancer cells (HepG2 and Huh-7), and colon cancer cells (LoVo). [SHP2ligand: ; LC3 Ligand: ; Linker: .]

SHP2 protein degrader-3 (Compound SA-8) exhibits antiproliferative activity against HeLa cells, with IC50 values of 5.59 μM at 24 hours, 4.25 μM at 48 hours, and 4.81 μM at 72 hours. At concentrations of 0-10 μM over 24-96 hours, it degrades SHP2 protein in HeLa cells in a time- and dose-dependent manner, achieving a DC50 of 3.22 μM and a maximum degradation efficiency (Dmax) of 80.47%. At 10 μM for 72 hours, it induces SHP2 protein degradation via the autophagy-lysosome pathway. Additionally, concentrations ranging from 1.1 to 30 μM over 72 hours can induce apoptosis in multiple cancer cell lines, including HeLa, HepG2, LoVo, and Huh-7 cells.