Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice

Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target

From ‘ivory tower traditionalists’ to ‘entrepreneurial scientists’? Academic scientists in fuzzy university-industry boundaries

Growing intensity of university-industry ties has generated an intense debate about the changing norms and practices of academic scientific work. This study challenges the protagonists’ views on the emergence of a dominant market ethos in academic science and growing influence of the ‘new school’ entrepreneurial scientists. It argues that academic scientists are active agents shaping the relationships between science and business, and shows continued diversity in their work orientations. Drawing on neo-institutional theory and the notion of ‘boundary work’, the study examines how scientists seek to protect and negotiate their positions, and also make sense of their professional role identities. It identifies four different orientations, the ‘traditional’ and ‘entrepreneurial’, with two hybrid types in between. The hybrids are the dominant category and are particularly adept at exploiting the ambiguities of ‘boundary work’ between academia and industry. The study is based on 36 interviews and a survey sample of 734 academic scientists from five UK research universities