Work Package: 6 – Test Programme Nature of Deliverable: RE- Report Authors:

Keywords: This deliverable reports of the results on the Quantum Test Programme which evaluates emerging technologies with the ultimate goal to understand how to implement operational services useful to the NRNs. It follows on from D6.1 in which the interim results of the QTP were summarised. Some of the activities outlined in D6.1 have not been developed further and are not therefore repeated herein, whilst other activities will continue to develop until the end of the Quantum project (October 2000) after which more results will be made available. This report focuses on the results obtained since publication of D6.1and outlines which activitie

First-in-class inhibitors of the ribosomal oxygenase MINA53

MINA53 is a JmjC domain 2-oxoglutarate dependent oxygenase that catalyzes ribosomal hydroxylation and which is a target of the oncogenic transcription factor c-MYC. Despite its anticancer target potential, no small molecule MINA53 inhibitors are reported. Using ribosomal substrate fragments, we developed mass spectrometry assays for MINA53 and the related oxygenase NO66. These enabled the identification of 2-(aryl)alkylthio-3,4-dihydro-4- oxoypyrimidine-5-carboxylic acids as potent MINA53 inhibitors, with selectivity over NO66 and other JmjC oxygenases. Crystallographic studies with the JmjC demethylase KDM5B, revealed active site binding, but without direct metal chelation; however, molecular modeling investigations indicate that the inhibitors bind to MINA53 by directly interacting with the iron cofactor. The MINA53 inhibitors manifest evidence for target engagement and selectivity for MINA53 over KDM4-6. The MINA53 inhibitors show antiproliferative activity with solid cancer lines, and sensitize cancer cells to conventional chemotherapy, suggesting further work investigating their potential in combination therapies is warranted

Alirocumab and cardiovascular outcomes after acute coronary syndrome

BACKGROUN

Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome

BACKGROUN