Design and development of novel antagonists targeting Cdc20, a central regulator of the Anaphase-Promoting Complex/Cyclosome, for the treatment of cancer
Cancer prevails as a worldwide healthcare concern, thus extensive investigations into innovative therapies remains the principal focus of medical research. A prevalent hallmark amongst diverse cancers is aneuploidy and genomic instability caused by chromosome missegregation ensuing a defective Spindle Assembly Checkpoint (SAC), a surveillance mechanism monitoring accurate chromosome-microtubule interactions during mitosis. Cell division cycle 20 (Cdc20), a central SAC regulator and mitotic protein, binds the Anaphase-Promoting Complex/Cyclosome (APC/C), a complex capable of stipulating protein destruction, regulating its activity and driving cell cycle progression through orderly APC/C substrate degradation. Key oncogenic roles and aberrant expression among diverse cancers, suggest Cdc20 a promising therapeutic target for the development of innovating cancer therapy strategies. Although numerous small compounds that supress Cdc20 expression have been reported in the literature, none are clinically approved and in addition, many are not truly Cdc20-specific. Thus, continuation of investigations into manipulating cancer cells mitotic exit attributable to targeting Cdc20 are vital and remain to be fully explored. The work presented in this thesis addresses this gap in knowledge, utilising a multidisciplinary approach to advance an early drug discovery campaign in the Bolanos-Garcia lab through integrating biochemical, biological and biophysical techniques with cell biology methods to develop novel small-size Cdc20 antagonists to treat cancer. The combinatorial approach undertaken, which integrates gene expression, protein biochemistry and protein biophysics with cell biology assays, has facilitated the screening of three de novo-designed generations of potential Cdc20 ligands. These advances have enabled the advancement of lead compounds that exhibit high potency in halting cell proliferation in Triple Negative Breast Cancer (TNBC) cells at low concentrations. Subsequently, one lead compound was selected for preclinical development studies involving deeper functional assays analysis and importantly confirmation of an adequate pharmacological profile. Therefore, a true potential as a bona fide lead molecule to develop novel anticancer drugs of higher efficacy than the current drugs approved for the treatment of TNBC. Thus, the work reported in this thesis provides a solid platform for the innovation of potent Cdc20 inhibitors as an improved alternative to current therapeutic strategies for cancers caused by chromosomal segregation defects.
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