PROTAC-Mediated Proteasomal Degradation of Src Homology 2 Domain–Containing Phosphatase 2 (SHP2) for Solid Tumor Therapy

Unlike liquid tumors such as leukemia and lymphoma, solid tumors are abnormal masses of tissue that grow in a solid shape. SHP2 protein, encoded by the PTPN11 gene, plays a crucial role in solid tumor development, progression, and metastasis by integrating signals from various membrane receptors and promoting cell survival and reproduction. Proteolysis targeting chimera (PROTACs) are molecules designed to degrade target proteins rather than inhibiting them and can be used in the proteasomal degra- dation of the SHP2 protein. We hypothesize that PROTAC P1 will bind firmly to the SHP2 and E3 Ligase protein. AlphaFold 3 was used to produce the SHP2 protein structure, while the PROTACs were modeled using YASARA software. Molecular docking simulations using HDOCK were performed to understand the protein-PROTAC interactions. Based on these interactions, chemical mutations were performed us- ing the CReM (Chemically Reasonable Mutations) webserver to generate a PROTAC mutant library. For each PROTAC mutation, PLIP was used to identify hydrophobic interactions and hydrogen bonds, while PRODIGY calculated the binding free energy. The binding energy of the mutant P1 PROTAC was high- est (-10.02 kcal/mol) and was selected for further pharmacokinetic and pharmacodynamic analysis. In future studies, we will be performing PROTAC optimization to enhance gastrointestinal absorption and bioavailability. The current research will help in designing novel PROTACs with improved binding affin- ity and optimized protein ligand interactions for enhanced therapeutic effectiveness against solid tumors.