2 research outputs found
Fragment-Based Discovery of Bromodomain Inhibitors Part 2: Optimization of Phenylisoxazole Sulfonamides
Bromodomains are epigenetic reader modules that regulate
gene transcription through their recognition of acetyl-lysine modified
histone tails. Inhibitors of this proteināprotein interaction
have the potential to modulate multiple diseases as demonstrated by
the profound anti-inflammatory and antiproliferative effects of a
recently disclosed class of BET compounds. While these compounds were
discovered using phenotypic assays, here we present a highly efficient
alternative approach to find new chemical templates, exploiting the
abundant structural knowledge that exists for this target class. A
phenyl dimethyl isoxazole chemotype resulting from a focused fragment
screen has been rapidly optimized through structure-based design,
leading to a sulfonamide series showing anti-inflammatory activity
in cellular assays. This proof-of-principle experiment demonstrates
the tractability of the BET family and bromodomain target class to
fragment-based hit discovery and structure-based lead optimization
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