Abstact

Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is an attractive therapeutic target in oncology and immunology-related disorders. However, developing novel phosphatase inhibitors that combine high potency, selectivity, cellular permeability, and drug-like properties remains challenging. The discovery of an allosteric mode of inhibition for SHP2 was a breakthrough, enabling the development of selective inhibitors that stabilize the phosphatase in its inactive conformation. We identified 2H-indazoles as a privileged and underexplored scaffold. Using our recently described palladium-catalyzed domino reaction as a key synthetic step, 3-amino-2H-indazoles were efficiently accessed from readily available precursors, enabling rapid exploration of novel allosteric inhibitors of SHP2. This approach led to compound 17g, a potent and selective allosteric SHP2 inhibitor (SHP2(WT) IC(50) = 49 nM). High-resolution structural characterization by X-ray crystallography revealed binding within the SHP2 allosteric tunnel. Consistent with its biological activity, compound 17g also effectively suppressed ERK phosphorylation in MV-4-11, Panc-1, and KYSE520 cells with an IC(50) of 50, 250, and 410 nM, respectively. These findings not only highlight the therapeutic potential of 2H-azaindazoles as a new class of SHP2 inhibitors but also underscore the importance of advances in efficient synthetic methodologies for constructing novel heterocyclic scaffolds and substitution patterns.