Jacqueline Elizabeth Mordaunt

Discovery of Epigenetic Regulator I-Bet762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the Bet Bromodomains.

The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.

Oxytocin antagonists as potential therapeutic agents for the treatment of preterm labour.

Publisher Summary The chapter illustrates the major advances that have been made in the oxytocin field. Modification of the natural hormone has led to peptide antagonists suitable for short-term intravenous administration in the acute treatment of preterm labor. One of these molecules, atosiban has been approved in Europe for this indication. Recently, non-peptidic antagonists with generally improved selectivity for the oxytocin receptor over the related vasopressin receptors and improved pharmacokinetic properties, including oral bioavailability, have been discovered. These molecules offer the prospect of much-improved therapeutic options for the distressing condition of preterm labor, which too frequently leads to the birth of very immature babies with very limited life expectancy or with major disabilities. Treatment of the mother in preterm labor with an oxytocin antagonist to achieve acute tocolysis, and then as maintenance for the critical last trimester of pregnancy may make a major difference to these parents and their offspring.