Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides

Paul Bamborough; Hawa Diallo; Jonathan D Goodacre; Laurie Gordon; Antonia Lewis; Jonathan T Seal; David M Wilson; Michael D Woodrow; Chun-Wa Chung

doi:10.1021/jm201283q

Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides

J Med Chem. 2012 Jan 26;55(2):587-96. doi: 10.1021/jm201283q. Epub 2012 Jan 11.

Authors

Paul Bamborough¹, Hawa Diallo, Jonathan D Goodacre, Laurie Gordon, Antonia Lewis, Jonathan T Seal, David M Wilson, Michael D Woodrow, Chun-Wa Chung

Affiliation

¹ Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Paul.a.Bamborough@gsk.com

PMID: 22136469
DOI: 10.1021/jm201283q

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Cell Cycle Proteins
Crystallography, X-Ray
Cytokines / biosynthesis
Fluorescence Polarization
Humans
Isoxazoles / chemical synthesis
Isoxazoles / chemistry
Isoxazoles / pharmacology
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / metabolism
Models, Molecular
Molecular Structure
Nuclear Proteins / chemistry
Protein Binding
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Solubility
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / pharmacology
Surface Plasmon Resonance
Transcription Factors / chemistry

Substances

Anti-Inflammatory Agents, Non-Steroidal
BRD2 protein, human
BRD4 protein, human
Cell Cycle Proteins
Cytokines
Isoxazoles
Nuclear Proteins
Sulfonamides
Transcription Factors
Protein Serine-Threonine Kinases

Associated data

PDB/4A9M
PDB/4A9N
PDB/4A9O
PDB/4A9P