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.

Son of sevenless homologue 1 (SOS1) protein is universally expressed in cells and plays an important role in the RAS signaling pathway. Specifically, this protein interacts with RAS in response to upstream stimuli to promote guanine nucleotide exchange in RAS and activates the downstream signaling pathways. Thus, targeting SOS1 is a new approach for treating RAS-driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of SOS1 and focus on recent advances in the discovery of activators, inhibitors, and PROTACs that target SOS1. This review aims to provide a timely and updated overview on the strategies for targeting SOS1 in cancer therapy.