The Molecular Mechanism Found in the Fact the Interaction of Skp1 with F-box is Disrupted by Small Molecules and Becomes a Potential Therapeutic Target for Lung Cancer
2022-08-04510CRLs are the largest family of ubiquitin proteasome system (UPS), and play an important role in many intracellular processes, physiology, and diseases (such as cancer). The SCF (Skp1-Cullin1-F-Box) complex is one of the most clearly studied members of CRLs, and has become a drug target for effective cancer therapy. Currently, the research on anticancer therapy targeting SCF is increasing day by day.
Recently, the research team led by Liu Jinsong, deputy director of the Laboratory, published an article titled “A small-molecule Skp1 inhibitor elicits cell death by p53-dependent mechanism” in iScience (Cell Press), reporting that a quinoline-derived small molecule of Z0933M can disrupt the function of SCF E3 ligase, further suggesting that SCF may become a target for cancer therapy. This study focuses on the new drug target for lung cancer therapy, Skp1, a central regulatory component of the SCF E3 ligase compound.
Using a hypothesis-driven structure-based design, this study identified Z0933M as a potential Skp1 inhibitor with a KD value of 54.7 ± 6.68 nM. In addition, the compound shows relatively high EC50 values for 22 tumor cell strains, with values ranging from 0.25 μ M to 4 μ M. Since Z0933M has a polycyclic structure that occupies a hydrophobic hotspot (P1) on the Skp1 C-terminal extended region, Z0933M can prevent the interaction between Skp1 and F-box proteins, which is a necessary step to assemble a complete and active SCF E3 ligase compound.
Intracellularly, Z0933M, by affecting the function of SCF E3 ligase, incurs the decline of polyubiquitination, which is consistent with previously reported effects caused by reduced Skp1 activity such as DNA damage, and elicits p53-dependent cell death. This work suggests that Z0933M can be used as a tool compound in the study of protein ubiquitination, as well as as a chemical probe for future lead drug optimization and anticancer drug development.
Schematic diagram of Z0993M inhibiting the SCF ubiquitin-ligase compound assembly and eliciting p53-dependent cell death by binding to Skp1
Contact:
Dr. Jinsong Liu (liu_jinsong@gibh.ac.cn)
