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Research overview

Professor Swen Hoelder, Medicinal Chemistry 4 Team

The main focus in our team is to apply our medicinal chemistry skills to discover innovative cancer drugs. To achieve that, we collaborate with other research teams, both internally within the unique environment of the ICR, and with external collaborators. A recent example is the MPS1 inhibitor BOS172722 that was designed and synthesised in our team. BOS172722 is currently undergoing Phase I clinical trials at The Royal Marsden Hospital for triple negative breast cancer, a disease that represents a high medical need. The MPS1 project was a highly interdisciplinary effort to which several teams at the ICR contributed.

Apart from focusing on clinical candidates, we are also keen to identify selective inhibitors as chemical probes as exemplified by BAZ2-ICR that we discovered in collaboration with the Structural Genomics Consortium. BAZ2-ICR was the first inhibitor to be published for the BAZ2 bromodomains. Tool compounds are invaluable to deepen our understanding of the role of the target in cancer.

Diagram showing key crystal structures of inhibitors

Images: Crystal structures of BOS172722 bound to MPS1 (left) and of BAZ2-ICR bound to BAZ2A (right)

We place a strong emphasis on applying rational design and in particular, we explore structural information to identify and optimise lead compounds. Examples are our recent publications on inhibitors of the kinase ACVR1, a target for a rare and aggressive paediatric brain cancer, and the BAZ2A/B bromodomains as well as dual kinase bromodomain inhibitors targeting ALK and BRD4 for the treatment of high risk neuroblastoma.

The team also has significant experience in late stage lead optimisation, particularly the utilisation of in vivo pharmacokinetic and pharmacodynamics data to deliver preclinical drug candidates as exemplified by the discovery of BOS172722.

To facilitate our drug discovery programs, we establish and develop synthetic approaches, for example a high yielding route that allowed upscaling of BOS172722 in the Kg range and a concise approach to a new type of stapled peptide.

A final but very import goal of the team is to train junior team members in medicinal chemistry, both through teaching of the scientific principles and through training on the job.


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