Structure-based design of Anaphase Promoting Complex/Cyclosome (APC/C) inhibitors as leads for drug development: an experimental and computational approach

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In light of a continuously increasing life expectancy, cancer imposes major challenges for society not only on a personal level but also for healthcare. The ubiquitin E3 ligase Anaphase Promoting Complex or Cyclosome (APC/C) is emerging as an attractive drugable target in cancer therapy to affect specifically rapidly dividing cancer cells as a first step for gaining specificity in treatment. As of today, however, there is no approved APC/C specific drug available. Here, in an interdisciplinary approach, we combine our strong expertise in cell cycle regulation and APC/C biology with structure-based de novo rational engineering to obtain lead molecules for drug development targeting the APC/C. Taking advantage of the recently available structural data on APC/C at atomic resolution, we have identified two molecular attack points based on its recognition properties towards proteins known to interfere with APC/C function. We apply biochemical and cell biological approaches to experimentally evaluate the inhibitory potential of structure-based rationally designed molecules. Our preliminary data obtained through a template-based rescaffolding strategy indicate that a first generation of designed molecules has already a strong inhibitory efficiency against APC/C in vitro. The proposed combination of state-of-the-art computational and experimental approaches in an iterative fashion is expected to provide potent and specific APC/C inhibitors with optimized properties as lead molecules for drug development for cancer treatment.