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The Rainwater grant has been signed

The Rainwater Charitable Foundation announces partnership with drug discovery teams at the University of Oxford.

Congratulations to our DPhil student Amber Truepenny

Massive congratulations to our DPhil student Amber Truepenny who won the inaugural Jamie Ferguson Chemistry Innovation Award. It’s a real testament to all her hard work on an exciting and challenging project - watch this space!

Congratulations to DPhil student Eva Dalietou

Congratulations to DPhil student Eva Dalietou, Bullock lab, for winning the best poster prize with her work showing how cofactors bind to the KLHL12 E3 ligase at the Ubiquitin & Friends Symposium 2022, which was organised by the University of Vienna’s SFB Targeted Protein Degradation program.

Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation (new paper published)

The Bullock lab has a new paper in Cell Death & Differentiation entitled “Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation”. During normal development, CoREST complexes containing LSD1, HDAC, and CoREST silence chromatin. In medulloblastoma, mutations in the E3 ligase KBTBD4 induce CoREST degradation thereby promoting increased transcription of stemness genes for tumorigenesis. The study builds on a CRUK-funded collaboration between the labs of Vincenzo D’Angiolella, Steve Clifford and Alex Bullock.

Sequence and structural variations determining the recruitment of WNK kinases to the KLHL3 E3 ligase (new paper published)

The Bullock lab has a new paper in Biochem J entitled “Sequence and structural variations determining the recruitment of WNK kinases to the KLHL3 E3 ligase”. Structural, biochemical and cellular data reveal how the KLHL3 Kelch domain can accommodate the binding of multiple WNK isoforms and highlight a potential regulatory mechanism for the recruitment of WNK3.

Fragment Hotspot Mapping to Identify Selectivity-Determining Regions between Related Proteins (new paper published)

CMD, CCDC and Exscientia, and Oxford University collaborate on an automated, quantitative method for informing the design of compound selectivity across protein families.

Ubiquitin ligases: guardians of mammalian development

The Bullock and Yamada labs have a new paper in Nature Reviews Molecular Cell Biology entitled “Ubiquitin ligases: guardians of mammalian development”. See https://www.nature.com/articles/s41580-021-00448-5. This Review discusses the crucial roles of E3 ubiquitin ligases during key steps of early mammalian development and their roles in human disease, and considers how new methods to manipulate and exploit the ubiquitin regulatory machinery — for example, the development of molecular glues and PROTACs — might facilitate clinical therapy.

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.

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