A Small-Molecule Skp1 Inhibitor Elicits Cell Death by p53-Dependent Mechanism

Skp1 overexpression promotes tumor growth and progression, while reduced Skp1 activity in some cancer cells is also linked with genomic instability and neoplastic transformation. These conflicted reports highlight the need to gain a 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 a KD of 54.7 ± 6.68 nM. Owing to its multicyclic architecture, 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 the previously reported effects of Skp1 reduced activity, and elicited cell death by p53-dependent mechanism. We propose Z0933M as a valuable tool for future efforts toward probing Skp1 cancer biology, with implications for cancer therapy.