Evaluating the Advantages of Using 3D-Enriched Fragments for Targeting BET Bromodomains

Jorden A. Johnson, Christos A. Nicolaou, Steven E. Kirberger, Anil K. Pandey, Haitao Hu, William C.K. Pomerantz

Research output: Contribution to journalArticle

Abstract

Fragment-based ligand discovery has been successful in targeting diverse proteins. Despite drug-like molecules having more 3D character, traditional fragment libraries are largely composed of flat, aromatic fragments. The use of 3D-enriched fragments for enhancing library diversity is underexplored especially against protein-protein interactions. Here, we evaluate using 3D-enriched fragments against bromodomains. Bromodomains are highly ligandable, but selectivity remains challenging, particularly for bromodomain and extraterminal (BET) family bromodomains. We screened a 3D-enriched fragment library against BRD4(D1) via 1H CPMG NMR with a protein-observed 19F NMR secondary assay. The screen led to 29% of the hits that are selective over two related bromodomains, BRDT(D1) and BPTF, and the identification of underrepresented chemical bromodomain inhibitor scaffolds. Initial structure-activity relationship studies guided by X-ray crystallography led to a ligand-efficient thiazepane, with good selectivity and affinity for BET bromodomains. These results suggest that the incorporation of 3D-enriched fragments to increase library diversity can benefit bromodomain screening.

Original languageEnglish (US)
Pages (from-to)1648-1654
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume10
Issue number12
DOIs
StatePublished - Dec 12 2019

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Libraries
Ligands
Proteins
X Ray Crystallography
Nuclear magnetic resonance
Protein Transport
Structure-Activity Relationship
X ray crystallography
Scaffolds
Assays
Screening
Pharmaceutical Preparations
Molecules
Proton Magnetic Resonance Spectroscopy

Keywords

  • 3D fragment screening
  • CPMG
  • F NMR
  • bromodomains
  • thiazepane

PubMed: MeSH publication types

  • Journal Article

Cite this

Evaluating the Advantages of Using 3D-Enriched Fragments for Targeting BET Bromodomains. / Johnson, Jorden A.; Nicolaou, Christos A.; Kirberger, Steven E.; Pandey, Anil K.; Hu, Haitao; Pomerantz, William C.K.

In: ACS Medicinal Chemistry Letters, Vol. 10, No. 12, 12.12.2019, p. 1648-1654.

Research output: Contribution to journalArticle

Johnson, Jorden A. ; Nicolaou, Christos A. ; Kirberger, Steven E. ; Pandey, Anil K. ; Hu, Haitao ; Pomerantz, William C.K. / Evaluating the Advantages of Using 3D-Enriched Fragments for Targeting BET Bromodomains. In: ACS Medicinal Chemistry Letters. 2019 ; Vol. 10, No. 12. pp. 1648-1654.
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