Jonathan Thomas Seal

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 protein-protein 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.

Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A).

A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model.

From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151.

The discovery, synthesis and biological evaluation of a novel series of 7-isoxazoloquinolines is described. Several analogs are shown to increase ApoA1 expression within the nanomolar range in the human hepatic cell line HepG2.

BET bromodomain inhibitors show anti-papillomavirus activity in vitro and block CRPV wart growth in vivo

ABSTRACT The DNA papillomaviruses infect squamous epithelium and can cause persistent, benign and sometimes malignant hyperproliferative lesions. Effective antiviral drugs to treat human papillomavirus (HPV) infection are lacking and here we investigate the anti‐papillomavirus activity of novel epigenetic targeting drugs, BET bromodomain inhibitors. Bromodomain and Extra‐Terminal domain (BET) proteins are host proteins which regulate gene transcription, they bind acetylated lysine residues in histones and non‐histone proteins via bromodomains, functioning as scaffold proteins in the formation of transcriptional complexes at gene regulatory regions. The BET protein BRD4 has been shown to be involved in the papillomavirus life cycle, as a co‐factor for viral E2 and also mediating viral partitioning in some virus types. We set out to study the activity of small molecule BET bromodomain inhibitors in models of papillomavirus infection. Several BET inhibitors reduced HPV11 E1ˆE4 mRNA expression in vitro and topical therapeutic administration of an exemplar compound I‐BET762, abrogated CRPV cutaneous wart growth in rabbits, demonstrating translation of anti‐viral effects to efficacy in vivo. Additionally I‐BET762 markedly reduced viability of HPV16 infected W12cells compared to non‐infected C33A cells. The molecular mechanism for the cytotoxicity to W12cells is unknown but may be through blocking viral‐dependent cell‐survival factors. We conclude that these effects, across multiple papillomavirus types and in vivo, highlight the potential to target BET bromodomains to treat HPV infection. HIGHLIGHTSWe show anti‐papillomavirus effects of BET bromodomain inhibitors, a new class of epigenetic drug.Several BET inhibitors reduced HVP11 E1ˆE4 transcription in a transient infection model in vitro.Topical delivery of BET inhibitor abrogated CRPV wart growth in rabbits, demonstrating translation to efficacy in vivo.BET inhibitor treatment reduced viability of HPV16 infected W12cells.Efficacy across multiple PV types and in vivo highlight potential to target BET bromodomains to treat HPV infection.