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. 2019 Nov 22;10(12):1648-1654.
doi: 10.1021/acsmedchemlett.9b00414. eCollection 2019 Dec 12.

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

Jorden A Johnson  1 , Christos A Nicolaou  2 , Steven E Kirberger  1 , Anil K Pandey  1 , Haitao Hu  2 , William C K Pomerantz  1
Affiliations

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

Jorden A Johnson et al. ACS Med Chem Lett. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(A) PBF and Fsp3 comparison of the 3D-enriched library and the proprietary traditional fragment library from Urick et al. and hits. (B) PBF analysis of 3D fragment 1, and a more 2D fragment, 2.
Figure 2
Figure 2
(A) Example PrOF NMR titration of 1 with BRD4(D1) (right). (B, C) Representative single point PrOF NMR spectra with 1 against BPTF (left) and BRDT(D1) (right) with corresponding protein structures and locations of the 5FW labels. (D) Fragment 1.
Figure 3
Figure 3
(A) Key interactions of 1 with BRD4(D1). PDB 6UWX. Structured waters are indicated as red spheres. (B) Overlay of 1 (gray) with (+)-JQ1 (cyan). (C) Key interactions of 30 with BRD4(D1). PDB 6UVJ. (D) Overlays of 1 (green) and 30 (purple).
Figure 4
Figure 4
Summary of PBF distribution of the 3D- and 2D-enriched libraries, and BRD4-binding fragments (MW < 300 g/mol) in the PDB. (A) Boxplot showing the distribution of PBF. Average PBF values are black. (B) Quantitative results of the Mann–Whitney–Wilcoxon (MWW) test showing the differences in PBF.
See this image and copyright information in PMC

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