Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors.

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• SHP2 is a crucial nonreceptor protein tyrosine phosphatase regulating cell growth, differentiation, and oncogenic transformation.
• SHP2 also plays a role in immune surveillance through the programmed cell death (PD-1/PD-L1) pathway.
• Small-molecule inhibition of SHP2 is an active area of research, with previous work identifying SHP099 as a binder to an allosteric site.

Purpose of the Study:

• To explore diverse allosteric inhibitors of SHP2 by expanding hit finding and scaffold morphing.
• To identify novel chemical scaffolds targeting the allosteric tunnel of SHP2.
• To characterize the structural diversity and in vivo efficacy of newly identified SHP2 inhibitors.

Main Methods:

• Hit finding and evaluation of small molecules targeting SHP2.
• Structure-based scaffold morphing to optimize binding to the allosteric tunnel.
• Characterization of pyrazolopyrimidinones, including SHP389, for their ability to modulate MAPK signaling.

Main Results:

• Identification of multiple 5,6-fused bicyclic scaffolds binding to the same allosteric tunnel as SHP099.
• Demonstration of structural diversity within the identified scaffolds.
• Discovery of pyrazolopyrimidinones (e.g., SHP389) that effectively modulate MAPK signaling in vivo.

Conclusions:

• Novel allosteric inhibitors of SHP2 based on 5,6-fused bicyclic scaffolds have been identified.
• Pyrazolopyrimidinones represent a promising class of SHP2 inhibitors with in vivo activity.
• These findings provide a foundation for further optimization of SHP2-targeted therapies.