Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisation.

Deubiquitinating enzymes (DUBs) are key regulators of cellular homoeostasis, and their dysregulation is associated with several human diseases. The ovarian tumour protease (OTU) family of DUBs are biochemically well-characterised and of therapeutic interest, yet only a few tool compounds exist to study their cellular function and therapeutic potential. Here we present a chemoproteomics fragment screening platform for identifying novel DUB-specific hit matter, that combines activity-based protein profiling with high-throughput chemistry direct-to-biology optimisation to enable rapid elaboration of initial fragment hits against OTU DUBs.

Regulatory landscape with U.S. patient requirements and Clinical Trial Diversity expectations.

The Food and Drug Administration (FDA) has an expectation that products filed for marketing authorization have to include data that are representative of the US patient population. Any foreign clinical data that is submitted has to represent an ethnically diverse population that is generated utilizing qualified Principal Investigators (PIs) and conducted according to Good Clinical Practices (GCP) requirements outlined in 21 CFR 312.120, Foreign clinical studies not conducted under an IND.

Targeting the ubiquitin system by fragment-based drug discovery.

The ubiquitin system contains a wealth of potential drug targets for many diseases and conditions, including neurodegenerative, immune, metabolic and developmental diseases, as well as multiple cancers. Despite years of research, relatively few clinical inhibitors or specific chemical probes for proteins within the ubiquitin system exist, with many interesting target proteins yet to be explored. Fragment-based drug discovery (FBDD) offers efficient and broad coverage of chemical space with small libraries, using covalent and non-covalent approaches.

The effect of HLA matching and donor relatedness on the risk of autoimmune haemolytic anaemia in haematopoietic stem cell transplant recipients: A systematic review and meta-analysis.

Recent studies have identified autoimmune haemolytic anaemia (AIHA) as a haematopoietic stem cell transplant (HSCT) complication that represents a significant cause of morbidity and mortality for these patients. In order to understand this autoimmune phenomenon, emerging research has focused on the prognostic factors associated with the development of the disorder. These studies have identified numerous possible associations with often contrasting and conflicting results.

A Probe for NLRP3 Inflammasome Inhibitor MCC950 Identifies Carbonic Anhydrase 2 as a Novel Target.

Inhibition of inflammasome and pyroptotic pathways are promising strategies for clinical treatment of autoimmune and inflammatory disorders. MCC950, a potent inhibitor of the NLR-family inflammasome pyrin domain-containing 3 (NLRP3) protein, has shown encouraging results in animal models for a range of conditions; however, until now, no off-targets have been identified. Herein, we report the design, synthesis, and application of a novel photoaffinity alkyne-tagged probe for MCC950 () which shows direct engagement with NLRP3 and inhibition of inflammasome activation in macrophages.