Novel PROTACs for degradation of SHP2 protein

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Protein tyrosine phosphatase SHP2 (a member of PTPs family) is implicated in various cancers, including leukemia, non-small cell lung cancer, and breast cancer.
• SHP2 is recognized as a critical target for novel anti-cancer drug development.
• Developing effective SHP2 inhibitors is of significant therapeutic importance.

Purpose of the Study:

• To design and synthesize novel Proteolysis-Targeting Chimeras (PROTACs) that recruit the E3 ligase Cereblon (CRBN) to induce SHP2 degradation.
• To evaluate the efficacy of these SHP2-targeting PROTACs in inhibiting cancer cell growth and inducing apoptosis.

Main Methods:

• Synthesis of PROTAC molecules by conjugating pomalidomide (a CRBN ligand) with SHP099 (an allosteric SHP2 inhibitor).
• In vitro evaluation of the synthesized compounds, including SP4, for their ability to inhibit cancer cell proliferation (e.g., Hela cells).
• Assessment of SHP2 protein degradation and induction of apoptosis in cancer cells treated with the PROTACs.

Main Results:

• The developed PROTAC molecule, SP4, demonstrated a 100-fold increase in activity compared to the parent inhibitor SHP099 against Hela cells.
• SP4 significantly inhibited cancer cell growth.
• SP4 effectively induced SHP2 protein degradation and promoted cancer cell apoptosis.

Conclusions:

• CRBN-recruiting PROTACs targeting SHP2 represent a potent therapeutic strategy with enhanced anti-cancer efficacy.
• SP4 exhibits significant potential for treating SHP2-related cancers through targeted protein degradation.
• Further investigation into SHP2-protacs holds promise for advancing cancer treatment.