Chemists Report New Allosteric SHP2 Inhibitors Built on an Azaindole Scaffold
- SHP2 is a cytosolic protein tyrosine phosphatase implicated in oncogenic RTK and immune checkpoint signaling, making it a closely watched cancer/immuno-oncology target.
- Earlier allosteric SHP2 inhibitors have reached clinical trials but can face resistance mutations or PK limitations, motivating further chemotype exploration.
- This preprint reports a new series of N-aryl-1H-azaindole-derived allosteric SHP2 inhibitors, shifting away from orthosteric (active-site) inhibition approaches.
💡 Points
That shallow, conserved catalytic pocket is exactly why orthosteric SHP2 programs never went anywhere in my hands—no surprise this moves allosteric. But the irony's real: clinical allosteric inhibitors like TNO155 already picked up resistance mutations right in that allosteric tunnel, so a new chemotype needs to show it escapes those hotspots, not just re-occupy the same pocket with a different scaffold.