Discovery of a Novel Src Homology‑2 Domain Containing Protein Tyrosine Phosphatase‑2 (SHP2) and Cyclin-Dependent Kinase 4 (CDK4) Dual Inhibitor for the Treatment of Triple-Negative Breast Cancer

The
treatment of triple-negative breast cancer (TNBC) remains a
huge clinical challenge and dual-targeted small-molecule drugs might
provide new therapeutic options for this type of breast cancer. In
this work, we discovered a series of SHP2 and CDK4 dual inhibitors
through a fused pharmacophore strategy and structural optimization.
Notably, lead compound 10 with excellent SHP2 (IC50 = 4.3 nM) and CDK4 (IC50 = 18.2 nM) inhibitory
activities effectively induced G0/G1 arrest to prevent the proliferation
of TNBC cell lines. Furthermore, compound 10 showed great in vivo pharmacokinetic properties (F =
45.8%) and exerted significant antitumor efficacy in the EMT6 syngeneic
mouse model. Western blotting and immunohistochemical analysis confirmed
that 10 effectively targeted on both SHP2 and CDK4 and
activated the immune response in tumors. These results indicate that
lead compound 10, as the first SHP2 and CDK4 dual inhibitor,
merits further development for treating TNBC.