摘要：SummarySkp1 overexpression promotes tumor growth, whereas reduced Skp1 activity is also linked with genomic instability and neoplastic transformation. This highlights the need to gain better understanding of Skp1 biology in cancer settings. To this context, potent and cellularly active small-molecule Skp1 inhibitors may be of great value. Using a hypothesis-driven, structure-guided approach, we herein identify Z0933M as a potent Skp1 inhibitor with KD∼0.054 μM. Z0933M occupies a hydrophobic hotspot (P1) – encompassing an aromatic cage of two phenylalanines (F101 and F139) – alongside C-terminal extension of Skp1 and, thus, hampers its ability to interact with F-box proteins, a prerequisite step to constitute intact and active SCF E3 ligase(s) complexes.In cellulo, Z0933M disrupted SCF E3 ligase(s) functioning, recapitulated previously reported effects of Skp1-reduced activity, and elicited cell death by a p53-dependent mechanism. We propose Z0933M as valuable tool for future efforts toward probing Skp1 cancer biology, with implications for cancer therapy.Graphical abstractDisplay OmittedHighlights•Z0933M manifests strong binding with Skp1 and inhibits Skp1-F-box PPIs•Z0933M interacts with a P1 hotspot alongside C-terminal extension of Skp1•Z0933M alters SCF E3 ligase functioning, leading to substrate accumulation/modulation•Z0933M causes cell-cycle arrest, and elicits cell death by p53-dependent mechanismDrugs; Pharmaceutical science; Chemistry; Organic chemistry; Biological sciences; Cell biology
