Structure-guided design of a domain-selective bromodomain and extra terminal N-terminal bromodomain chemical probe

Small molecule mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain dataset through a lipophilic efficiency lens, which enabled identification of a BD1 domain biased benzimidazole series. Structure guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300–1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition

Structure-based design of a bromodomain and extraterminal domain (BET) inhibitor selective for the N-terminal bromodomains that retains an anti-inflammatory and antiproliferative phenotype

The bromodomain and extraterminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT), each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity, resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, the development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, we report the discovery of a potent probe molecule possessing up to 150-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided by structural information, a specific amino acid difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Data presented herein demonstrate that selective inhibition of BD1 domains is sufficient to drive anti-inflammatory and antiproliferative effects

Smartline Environmental Sensor Data and Utility Usage, 2017–2023

The Smartline sensor datasets include utility usage (Gas, Water, Electricity), indoors environmental parameters (Temperature, Humidity, TVOC - Total Volatile Organic Compounds, eCO2 - Estimated Carbon Dioxide, P.M2.5 - Airborne Particulate Matter More than 300 households were recruited in 2017 to take part in the Smartline project to provide data on health, wellbeing, community, indoor environment and utility usages. The overarching aim of the project was to explore and trial opportunities for technology to support people to live healthier and happier lives in their homes and communities. 329 households completed survey questionnaires and 279 opted to have sensors installed. The network of sensors, from which the accompanying data derive, provide opportunities to gain insight in to existing utility usage and environmental conditions in homes. Surveys of participating households were undertaken at several points in the project and linked to sensor data, enabling better exploration of the everyday human lives behind the sensor data. Many of the sensors have recorded data spanning more than 5 years, capturing regular patterns resulting from participants daily routines, seasonal climatic variation, and local weather activity. Unexpected events such as the Covid-19 pandemic, cost of living crisis, and a record summer heatwave all fall within the timeframe of the sensor data.</p