Discovery of SHP2-D26 as a First, Potent, and Effective PROTAC Degrader of SHP2 Protein

Src
homology 2 domain-containing phosphatase 2 (SHP2) is an attractive
therapeutic target for human cancers and other human diseases. Herein,
we report our discovery of potent small-molecule SHP2 degraders whose
design is based upon the proteolysis-targeting chimera (PROTAC) concept.
This work has led to the discovery of potent and effective SHP2 degraders,
exemplified by SHP2-D26. SHP2-D26 achieves DC50 values
of 6.0 and 2.6 nM in esophageal cancer KYSE520 and acute myeloid leukemia
MV4;11 cells, respectively, and is capable of reducing SHP2 protein
levels by >95% in cancer cells. SHP2-D26 is >30-times more potent
in inhibition of phosphorylation of extracellular signal-regulated
kinase (ERK) and of cell growth than SHP099, a potent SHP2 inhibitor,
in KYSE520 and MV4;11 cancer cell lines. This study demonstrates that
induced SHP2 degradation is a very effective approach to inhibit the
function of SHP2. Further optimization of these SHP2 degraders may
lead to the development of a new class of therapies for cancers and
other human diseases.