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DOS Report Summary

Project ID: 279337
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Final Report Summary - DOS (Drugging the Undruggable: Discovery of Protein-Protein Interaction Modulators Using Diversity-Oriented Synthesis)

We have pioneered the development of innovative chemistry-centred methods for the discovery of novel small molecules that probe challenging biological processes of significant therapeutic relevance.

We have developed several new diversity-oriented synthesis (DOS) platforms for the synthesis of structurally diverse small molecule libraries. Advanced branching DOS strategies allowed the generation of novel, diverse and complex small molecules from readily accessible diazoacetates. The DOS compounds displayed a high sp3 content, with scaffolds that are drug-like but that are more three-dimensional in character than drugs. This is notable, as the lack of three-dimensionality is considered to be a major drawback of typical small molecule screening collections. Biological evaluation of our compounds led to the discovery of the drug-like molecule ‘dosabulin’, which causes mitotic arrest and cancer cell death by apoptosis. This new structural class of antimitotic has a microtubule depolymerisation mechanism of action, which is common to mitotic inhibitors in clinical use. Antimitotic compounds have been used clinically for decades and this target class is widely regarded to still hold great potential for anti-cancer therapy. However, resistance and administration problems have increased the requirement for new therapies. Further investigations led to the development of a new, synthetically interesting domino reaction sequence that provides efficient access to a previously unreported and complex sp3-rich tetracyclic scaffold. Molecules of this sort also showed antimitotic activity, with no evidence of disruption to the tubulin network. Thus, the novel scaffold may define a new structural class of antimitotic with a novel mode of action.

Macrocyclic scaffolds are underrepresented in many synthetic libraries and this structural class is widely regarded to have untapped potential in drug discovery. We have made notable advancements in the field of macrocycle synthesis. A new approach for the DOS of macrocyclic peptidomimetics was developed, which enabled synthesis of over 200 scaffolds. This represented a step-change in the degree of scaffold diversity incorporated in a synthetically-derived small molecule library. In other work, the DOS diverse drug-like macrocyclic scaffolds was achieved using a synthetically interesting orthogonal organo- and metal-catalysis strategy. We have also pioneered the concept of multidimensional coupling in DOS, a branching-type diversification process which leads to a greater structural diversity in the final macrocycle library. Further research led to the development of a more advanced synthesis concept, termed multi-dimensional DOS, featuring the extensive application of branching multidimensional diversification throughout the synthesis. Application of this approach enabled step-efficient generation of novel, structurally diverse, and highly-functionalised natural product-like macrocycles based around a broad range of scaffolds. It is anticipated that the multidimensional concept will have broad strategic value in DOS. Our macrocyle research has led to the development of several novel methodologies which may valuable in a wider synthetic context.

Protein-protein interactions (PPIs) represent a rich source of new potential drug targets. However, traditional ‘drug-like’ small molecules have proven to be largely unsuitable for PPI modulation. Our DOS research provided us with structurally atypical (more diverse and complex) small molecules to target PPIs. Efforts focused upon the proteins Gankyrin and Aurora-A. These proteins are overexpressed in many cancers and we targeted PPIs that are known to play a key role in regulating their activities (the Gankyrin:S6 interaction and the Aurora-A:TPX2 interaction), since the development of inhibitors of these PPIs could lead to new anticancer agents. Screening of our DOS libraries led to the discovery of novel small molecules termed ‘cjoc42’ and ‘AurkinA’ that can modulate these PPIs and thereby inhibit the normal activities of these proteins. It was determined that AurkinA acts via a novel mechanism of allosteric inhibition, which has significant implications for the selective therapeutic targeting of structurally related kinases.


Renata Schaeffer, (The Chancellor, Masters and Scholars of The University of Cambridge)
Tel.: +441223333543
Fax: +441223332988
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