2 research outputs found
Discovery of Epigenetic Regulator IāBET762: 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 structureāactivity 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
The Discovery of IāBET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor
Through
their function as epigenetic readers of the histone code,
the BET family of bromodomain-containing proteins regulate expression
of multiple genes of therapeutic relevance, including those involved
in tumor cell growth and inflammation. BET bromodomain inhibitors
have profound antiproliferative and anti-inflammatory effects which
translate into efficacy in oncology and inflammation models, and the
first compounds have now progressed into clinical trials. The exciting
biology of the BETs has led to great interest in the discovery of
novel inhibitor classes. Here we describe the identification of a
novel tetrahydroquinoline series through up-regulation of apolipoprotein
A1 and the optimization into potent compounds active in murine models
of septic shock and neuroblastoma. At the molecular level, these effects
are produced by inhibition of BET bromodomains. X-ray crystallography
reveals the interactions explaining the structureāactivity
relationships of binding. The resulting lead molecule, I-BET726, represents
a new, potent, and selective class of tetrahydroquinoline-based BET
inhibitors