Podcast: Understanding growth signals

My research aims to understand the signalling mechanisms and disease-causing mutations that alter cell growth and differentiation and how these might be targeted by small molecule inhibitors to address devastating rare diseases and cancer.

My primary focus is on proteins mediating phosphorylation and ubiquitylation and applies multidisciplinary techniques in structural, chemical and cellular biology. A particular interest has been the receptor serine/threonine kinase ACVR1/ALK2. Mutations in this receptor drive the childhood brain tumour diffuse midline glioma, as well as the musculoskeletal disorder fibrodysplasia ossificans progressiva (FOP). My group has elucidated the structural basis of disease-causing mutations and identified a number of small molecule inhibitors that block the aberrant ALK2 signalling found in disease models. We are currently conducting a phase 2 clinical trial of the ALK2 inhibitor saracatinib for FOP patients in collaboration with clinicians in the UK, The Netherlands, Germany, and the US.

My work has also revealed a novel mechanism of tumorigenesis through E3 ligase neofunction. We discovered that mutations in the E3 ligase KBTBD4 alter its substrate specificity resulting in the KBTBD4-dependent degradation of the CoREST/LSD1/HDAC complex and epigenetic reprogramming in medulloblastoma. This work identifies KBTBD4 as a new druggable target for tumour-specific therapies. E3 ligases are also attractive targets for the design of small molecule PROTACs, bivalent chemical binders that recruit neo-substrates to an E3 ligase for targeted protein degradation. This approach has potential advantages over traditional occupancy-based inhibitors with respect to efficacy, side effects, and modulating 'undruggable' targets. We aim to develop small molecule binders for novel E3 ligases to expand the repertoire of E3s suitable for PROTAC development to maximise the potential of this technology.

I received my degree and PhD from the University of Cambridge where I trained with Sir Alan Fersht determining how cancer-associated mutations disrupt p53 folding. I was subsequently awarded a Wellcome Fellowship which I held first with David Baker at the University of Washington, Seattle, showing how the Rosetta software can be applied for protein interface design, and later with Sir Peter Ratcliffe at the University of Oxford for work on VHL proteomics and the oxygen-dependence of hypoxia signalling factor FIH. I joined the Structural Genomics Consortium (SGC) at its launch in 2004, working initially as a team leader with Stefan Knapp, before establishing my own research group in 2008.

I work closely with disease foundations, most recently FOP Friends and The Brain Tumour Charity, and contribute to public engagement, including pieces for radio, TV and film documentary. My own interest in medicines discovery was ignited after receiving a bone marrow transplant for relapsed leukaemia as a teenager and time spent in the Royal Free and St Bartholomew's hospitals.