Development of Potent SHP2 Allosteric Inhibitors: Design, Synthesis, and Evaluation with Antitumor Effects

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is crucial for cell signaling.
• SHP2 overexpression is linked to various cancers, necessitating targeted therapies.

Purpose of the Study:

• To design and synthesize novel allosteric SHP2 inhibitors.
• To evaluate the inhibitory potential and antitumor activity of new chemical entities.

Main Methods:

• Active fragment splicing approach for inhibitor design.
• Synthesis of thiazolo[5,4-b]pyridine and imidazo[1,2-c]pyrimidine derivatives.
• In vitro enzyme inhibition assays and in vivo xenograft studies.

Main Results:

• Novel derivatives demonstrated potent SHP2 inhibition (IC50: 9.0-34.5 nM).
• Compound B8 exhibited significant potency and modulated p-ERK signaling (IC50: 0.04 μM).
• Compound B8 displayed favorable drug-like properties and antitumor efficacy in a mouse model.

Conclusions:

• The developed compounds are effective allosteric SHP2 inhibitors.
• Compound B8 represents a promising lead candidate for SHP2-targeted cancer therapy.
• This study provides a basis for advancing SHP2-targeted therapeutics.