From Pyrazolones to Azaindoles: Evolution of Active-Site SHP2 Inhibitors Based on Scaffold Hopping and Bioisosteric Replacement

The tyrosine phosphatase SHP2 controls
the activity of pivotal
signaling pathways, including MAPK, JAK-STAT, and PI3K-Akt. Aberrant
SHP2 activity leads to uncontrolled cell proliferation, tumorigenesis,
and metastasis. SHP2 signaling was recently linked to drug resistance
against cancer medications such as MEK and BRAF inhibitors. In this
work, we present the development of a novel class of azaindole SHP2
inhibitors. We applied scaffold hopping and bioisosteric replacement
concepts to eliminate unwanted structural motifs and to improve the
inhibitor characteristics of the previously reported pyrazolone SHP2
inhibitors. The most potent azaindole 45 inhibits SHP2
with an IC50 = 0.031 μM in an enzymatic assay and
with an IC50 = 2.6 μM in human pancreas cells (HPAF-II).
Evaluation in a series of cellular assays for metastasis and drug
resistance demonstrated efficient SHP2 blockade. Finally, 45 inhibited proliferation of two cancer cell lines that are resistant
to cancer drugs and diminished ERK signaling.