Publications by authors named "D S Hargreaves"
Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether and biaryl as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CL compounds while maintaining a WT selectivity margin.
View Article and Find Full Text PDFBackground: Little is known about how GP consultation rates for children's respiratory tract infections (RTIs) have changed since the covid-19 pandemic restrictions lifted.
Aim: To describe changes in GP consultation rates for RTIs in children <5 years from 2016-2023.
Design And Setting: Population-based retrospective cohort study using electronic health records.
Article Synopsis
- BFL1, an antiapoptotic protein from the BCL2 family, is linked to hematological cancers but hasn't been extensively researched.
- Two articles present the development of selective BFL1 inhibitors, starting from hit identification using a covalent fragment library and leading to optimized compounds.
- One compound not only induced cell death in specific cancer cell lines but also stabilized the BFL1 protein, significantly increasing its half-life to 10.8 hours while activating cellular apoptosis markers.
Article Synopsis
- The study aimed to explore the vaccination rates and effectiveness of SARS-CoV-2 vaccines in children and young people (CYP) with life-limiting neurodisabilities using national hospital data from England between December 2020 and September 2022.
- Out of 38,067 CYP identified, only 35% received at least one vaccine dose, with higher uptake in older, white children from less deprived areas; upon follow-up, vaccination did not significantly lower hospitalization rates after COVID-19 infection.
- The vaccine showed significant protection against COVID-19 hospitalizations specifically during the Alpha-Delta variant phase, but had no impact during the Omicron variant phase, highlighting low vaccine uptake and disparities in vaccination by ethnicity and socio
Article Synopsis
- The study focuses on optimizing inhibitors for epidermal growth factor receptor (EGFR) Exon20 insertions (Ex20Ins) using structure-based drug design (SBDD).
- A new compound was discovered that is both effective against EGFR Ex20Ins and able to cross the blood-brain barrier in preclinical tests.
- The design process involved creating a novel bicyclic structure, making strategic modifications to improve stability and enhance brain exposure by refining key molecular properties.