Design, Synthesis, and Characterization of I-BET567, a Pan-Bromodomain and Extra Terminal (BET) Bromodomain Oral Candidate.

Through regulation of the epigenome, the bromodomain and extra terminal (BET) family of proteins represent important therapeutic targets for the treatment of human disease. Through mimicking the endogenous N-acetyl-lysine group and disrupting the protein-protein interaction between histone tails and the bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes the medicinal chemistry strategy and execution to deliver an orally bioavailable tetrahydroquinoline (THQ) pan-BET candidate. Critical to the success of this endeavor was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors within the GSK collection which enabled identification of appropriate lipophilicity space to deliver compounds with a higher probability of desired oral candidate quality properties. SAR knowledge was leveraged via Free-Wilson analysis within this design space to identify a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy in mouse models of oncology and inflammation.

GSK789: A Selective Inhibitor of the First Bromodomains (BD1) of the Bromo and Extra Terminal Domain (BET) Proteins.

Pan-bromodomain and extra terminal (BET) inhibitors interact equipotently with all eight bromodomains of the BET family of proteins. They have shown profound efficacy in vitro and in vivo in oncology and immunomodulatory models, and a number of them are currently in clinical trials where significant safety signals have been reported. It is therefore important to understand the functional contribution of each bromodomain to assess the opportunity to tease apart efficacy and toxicity. This article discloses the in vitro and cellular activity profiles of GSK789, a potent, cell-permeable, and highly selective inhibitor of the first bromodomains of the BET family.

Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease.

The discovery and lead optimisation of a novel series of SYK inhibitors is described. These were optimised for SYK potency and selectivity against Aurora B. Compounds were profiled in a human skin penetration study to identify a suitable candidate molecule for pre-clinical development. Compound 44 (GSK2646264) was selected for progression and is currently in Phase I clinical trials.

Intra-peritoneal mature benign cystic teratoma deposits: an unusual complication from previous surgical resection of an ovarian mature benign cystic teratoma.

In this case, we describe multiple unusual intra-peritoneal lesions containing fat, soft tissue and calcification. These were found radiologically and histologically to be in keeping with mature benign cystic teratoma intra-peritoneal deposits, also described as dermoid cysts. These were presumed to be due to seeding from surgical resection of ovarian mature benign cystic teratoma 5 years previously. This surgical complication has not been well documented thus far in the literature.

Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation.

PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of human and mouse PAD4 in both histone citrullination and neutrophil extracellular trap formation for, to our knowledge, the first time. The therapeutic potential of PAD4 inhibitors can now be explored.

The "Haunt" project: an attempt to build a "haunted" room by manipulating complex electromagnetic fields and infrasound.

Recent research has suggested that a number of environmental factors may be associated with a tendency for susceptible individuals to report mildly anomalous sensations typically associated with "haunted" locations, including a sense of presence, feeling dizzy, inexplicable smells, and so on. Factors that may be associated with such sensations include fluctuations in the electromagnetic field (EMF) and the presence of infrasound. A review of such work is presented, followed by the results of the "Haunt" project in which an attempt was made to construct an artificial "haunted" room by systematically varying such environmental factors. Participants (N=79) were required to spend 50 min in a specially constructed chamber, within which they were exposed to infrasound, complex EMFs, both or neither. They were informed in advance that during this period they might experience anomalous sensations and asked to record on a floor plan their location at the time of occurrence of any such sensations, along with a note of the time of occurrence and a brief description of the sensation. Upon completing the session in the experimental chamber, they were asked to complete three questionnaires. The first was an EXIT scale asking respondents to indicate whether or not they had experienced particular anomalous sensations. The second was the Australian Sheep-Goat Scale, a widely used measure of belief in and experience of the paranormal. The third was Persinger's Personal Philosophy Inventory, although only the items that constitute the Temporal Lobe Signs (TLS) Inventory sub-scale were scored. These items deal with psychological experiences typically associated with temporal lobe epilepsy but normally distributed throughout the general population. Although many participants reported anomalous sensations of various kinds, the number reported was unrelated to experimental condition but was related to TLS scores. The most parsimonious explanation for our findings is in terms of suggestibility.