Selective Fragments for the CREBBP Bromodomain Identified from an Encoded Self-assembly Chemical Library

ChemMedChem. 2020 Sep 16;15(18):1752-1756. doi: 10.1002/cmdc.202000528. Epub 2020 Aug 19.

Abstract

DNA-encoded chemical libraries (DECLs) are collections of chemical moieties individually coupled to distinctive DNA barcodes. Compounds can be displayed either at the end of a single DNA strand (i. e., single-pharmacophore libraries) or at the extremities of two complementary DNA strands (i. e., dual-pharmacophore libraries). In this work, we describe the use of a dual-pharmacophore encoded self-assembly chemical (ESAC) library for the affinity maturation of a known 4,5-dihydrobenzodiazepinone ring (THBD) acetyl-lysine (KAc) mimic for the cyclic-AMP response element binding protein (CREB) binding protein (CREBBP or CBP) bromodomain. The new pair of fragments discovered from library selection showed a sub-micromolar affinity for the CREBBP bromodomain in fluorescence polarization and ELISA assays, and selectivity against BRD4(1).

Keywords: CREBBP bromodomain; DNA-encoded chemical library; encoded self-assembly chemical library; inhibitors; medicinal chemistry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzodiazepinones / chemical synthesis
  • Benzodiazepinones / chemistry
  • Benzodiazepinones / pharmacology*
  • CREB-Binding Protein / antagonists & inhibitors*
  • CREB-Binding Protein / metabolism
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism

Substances

  • BRD4 protein, human
  • Benzodiazepinones
  • Cell Cycle Proteins
  • Small Molecule Libraries
  • Transcription Factors
  • CREB-Binding Protein
  • CREBBP protein, human