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2021 CMD Student Symposium

The 2021 CMD Oxford Student Symposium was a great day full of exciting science from our fantastic students! Special thanks to the student organisers and chairs, for hosting a seamless & exciting day, & congratulations to our prize winners!

Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection

From the Sanyal & Kessler labs and collaborators, read about our research findings on the biology of cytokine storms triggered by SARS-CoV-2.

Ubiquitin protease 28, a potential drug target in squamous lung carcinoma

The Behrens (ICR) and Kessler labs show that ubiquitin-specific protease 28 (USP28) is required for the survival of lung squamous cell carcinomas (LSCCs). Using genetic knockout models and a novel small molecule inhibitor of USP28, we demonstrate loss or inhibition of USP28 impairs the growth of LSCCs to a much greater degree than lung adenocarcinomas, associated with a greater degree of loss of c-MYC, c-JUN, and DP63. This work will be of interest to researchers seeking to better understand and treat LSCCs.

How can X-ray technology help in Covid research?

Professor Frank von Delft is co-founder of the Moonshot project, which is a collaboration of expertise from all over the world. Thanks to the light beam work at Diamond, chemists now know the virus' weak spots and can work on developing a new anti-viral drug.

Crystal Structure-Guided Design of Bisubstrate Inhibitors and Photoluminescent Probes for Protein Kinases of the PIM Family

The Bullock group is happy to contribute to this new report by Nonga et al describing the crystal structure-guided design of bisubstrate inhibitors and photoluminescent probes for protein kinases of the PIM Family.

Chemogenomics for drug discovery: clinical molecules from open access chemical probes

A key focus of the CMD is the development of small molecule chemical probes to investigate the biology of interesting, disease-relevant protein targets. An often touted benefit of probes is that they accelerate the drug discovery process by providing a starting point for small molecule drugs, but is this really the case? This review seeks to answer that question by describing a number of probes that have gone on to inspire a variety of clinical molecules, and will hopefully encourage drug discoverers to turn to chemical probes for inspiration.

Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva

Saracatinib is a clinically-tested dual Src/Abl kinase inhibitor. A new paper from Ellie Williams and the Growth Factor Signalling and Ubiquitination group led by Alex Bullock shows that saracatinib is an equipotent ALK2 kinase inhibitor. The paper outlines preclinical work that supports a current phase 2 clinical trial (NCT04307953) exploring the potential of saracatinib to treat cases of fibrodysplasia ossificans progressiva (FOP) driven by gain of function ALK2 mutations.

Deubiquitinase (DUB) profiling goes high-throughput

The Kessler group describes a new methodology named ABPP-HT (high-throughput-compatible activity-based protein profiling), implementing a semi-automated proteomic workflow to profile a panel of deubiquitylating enzyme (DUB) inhibitors in cells. This allows direct cellular target engagement of small molecules against cellular DUBs, thereby accelerating DUB drug discovery.

Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva

The Bullock Lab at CMD Oxford were delighted to be a part of this review from LUMC Leiden on Fibrodysplasia ossificans progressiva; an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites.

Exscientia and the University of Oxford announce partnership to develop treatments for Alzheimer’s disease

Neuroinflammation collaboration targeting inflammasome steps-up-the-pace in race for Alzheimer’s disease medicines that alleviate the burden of devastating disease.

ALK2 Receptor Kinase Association with FKBP12.6 Is Structurally Conserved with the ALK2-FKBP12 Complex

CMD postdoc Ellie Williams has published her structure of the ALK2 receptor kinase bound to FKBP12.6 and dorsomorphin in the journal Biomedicines.

The Bloom syndrome complex senses RPA-coated single-stranded DNA to restart stalled replication forks (new paper published)

Collaboration between CMD and Andy Blackford's team in @NatureComms describes how the DNA helicase mutated in Bloom syndrome (BLM) interacts with RPA, as well as which functions of BLM are important for the development of cancer.

The deubiquitylase USP9X controls ribosomal stalling (new paper published)

When a ribosome stalls during translation, it runs the risk of collision with a trailing ribosome. We have developed a specific small-molecule inhibitor of the deubiquitylase USP9X, linking USP9X with centrosome-associated protein stability Following chemical inhibition of its catalytic activity, levels of Makorins and ZNF598 are diminished, and the ribosomal quality control pathway is impaired. Benedikt Kessler's team at CMD/TDI was part of this study.

Oxford ramps up COVID-19 testing capability

The University of Oxford has joined forces with Thermo Fisher Scientific, the world leader in serving science, to ramp up the university’s capacity to deliver COVID-19 testing data.

Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers (new paper published)

Loss of WRN, a DNA repair helicase, was identified as a strong vulnerability of microsatellite instable (MSI) cancers, making WRN a promising drug target.

TBXT: A new Target Enabling package for rare disease

The Target Enabling Packages (TEPs) Programme continues to elucidate and enable novel targets for drug development.

Structural Biology identifies new information to accelerate structure-based drug design against Covid-19

A new paper in Nature Communications outlines how an international research team has identified potential ways forward to rapidly design improved and more potent compounds in the fight against COVID-19.

Wyatt Yue awarded 2021 Harrington UK Rare Disease Scholar Awards

The Harrington Discovery Institute in the US has announced five winners of its inaugural UK Rare Disease Scholar Award competition.

CMD begins project to revolutionise drug discovery using AI

The Centre for Medicines Discovery and King Abdulaziz University (KAU) have launched a major collaboration to accelerate medicines discovery using AI technologies, for diseases with unmet need, including rare diseases and cardio-metabolic diseases.

COVID Moonshot – aiming to develop novel small molecule inhibitors targeting SARS-CoV-2

A large collaborative initiative to contribute to the global anti- COVID-19 effort.

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