Discovery of a novel Fam20C inhibitor for treatment of triple-negative breast cancer

Sequence similarity 20 family member C (Fam20C), a Golgi casein kinase, has a gradually elucidated mechanism in triple-negative breast cancer (TNBC) and is considered a possible target for therapeutic intervention. In this study, we combined virtual screening and chemical synthesis methods to obtain a new small-molecule Fam20C inhibitor, compound 5k, which possesses desirable kinase inhibitory activity against Fam20C and significant anti-proliferative activity against MDA-MB-231 and BT-549 cells. Subsequently, cellular thermal shift assay (CETSA), molecular docking, and molecular dynamics (MD) simulations revealed that compound 5k binds to Fam20C. Moreover, compound 5k showed favorable antitumor efficacy in TNBC cells and xenograft models by promoting apoptosis and inhibiting migration. Mechanistically, compound 5k can inhibit the proliferation, promote apoptosis, and inhibit migration of TNBC cells by targeting Fam20C, thereby inhibiting the deterioration of TNBC and preventing its progression. Taken together, these results suggest that compound 5k can be utilized as a novel Fam20C inhibitor, laying a foundation for the discovery of more small-molecule drugs for the treatment of TNBC in the future.