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J. Med. Chem. 61(19), 8504-8535. Emerging Approaches for the Identification of Protein Targets of Small Molecules - A Practitioners’ Perspective. 2018

Comess, K.M., McLoughlin, S.M., Oyer, J.A., Richardson, P.L., Stöckmann, H., Vasudevan, A., and Warder, S.E.

Notes: This review delves into the drug discovery pipeline, focusing on both phenotypic drug discovery (PDD) and target-based drug discovery (TDD) and the importance of experiments which determine the mechanism of action (MOA) of drugs. NanoBRET is highlighted as a highly specific assay for the measurement of target interaction. Specifically, the precise tagging of a target greatly minimizes assay cross-talk. (5122)

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Nat Chem. Biol. 12(12), 1097–1104. Potent and selective bivalent inhibitors of BET bromodomains. 2016

Waring, M.J., Chen, H., Rabow, A.A., Walker, G., Bobby, R., Boiko, S., Bradbury, R.H., Callis, R., Clark, E., Dale, I., Daniels, D.L., Dulak, A., Flavell, L., Holdgate, G., Jowitt, T.A., Kikhney, A., McAlister, M., Méndez, J., Ogg, D., Patel, J., Petteruti, P., Robb, G.R., Robers, M.B., Saif, S., Stratton, N., Svergun, D.I., Wang, W., Whittaker, D., Wilson, D.M. and Yao, Y.

Notes: The bromodomain and extraterminal (BET) family of proteins contain two bromodomains. A probe compound, biBET, capable of binding both bromodomains of BET proteins in cis is characterized. BDR4-NanoLuc and Halo-tagged histone H3 fusions are used to monitor biBET binding with the NanoBRET Target Engagement system. Interestingly, bivalent binding lead to slower displacement of inhibitor from BDR4 and increased potency. (5078)

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Anal. Biochem. 489, 1–8. A luminescent assay for real-time measurements of receptor endocytosis in living cells. 2015

Robers, M. B., Binkowski, B. F., Cong, M., Zimprich, C., Corona, C., McDougall, M., Otto, G., Eggers, C. T., Hartnett, J., Machleidt, T., Fan, F. and Wood, K. V.

Notes: The authors describe a new method for real-time analysis of ligand-mediated receptor endocytosis in living cells. They used a BRET-based assay to detect the interactions of ligands with various GPCRs fused to NanoLuc® luciferase. (4693)

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Nature Methods 12(7), 661–663. Application of BRET to monitor ligand binding to GPCRs. 2015

Stoddart, L.A., Johnstone, E.K.M., Wheal, A.J.,  Goulding, J., Robers, M.B., Machleidt, T., Wood, K.V., Hill, S.J., and Pfleger, K.D.G.

Notes: These authors describe a new method for monitoring ligand binding to GPCRs on the surface of living cells. They used NanoLuc luciferase in a BRET-based assay to detect the interactions of ligands with the receptors with an N-terminal NanoLuc fusion. (4589)

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Nat. Commun. 6, 10091 doi:10.1038/ncomms10091. Target engagement and drug residence time can be observed in living cells with BRET. 2015

Robers, M.B, Dart, M.L., Woodroofe, C.C,  Zimprich, C.A., Kirkland, T.A., Machleidt, T., Kupcho, K.R., Levin, S., Hartnett, J.R., Zimmerman, K., Niles, A.L., Ohana, R.F., Daniels, D.L., Slater, M., Wood, M.G., Cong, M., Cheng Y., and Wood, K.V.

Notes: This paper describes a method for using bioluminescence resonance energy transfer (BRET) to reveal the binding characteristics of a drug with selected targets in live cells. The authors used cell-permeable fluorescent tracers in a competitive binding assay to quantify drug engagement with target proteins fused to Nanoluc luciferase. Using this approach, they were able to profile isozyme-specific engagement and binding kinetics for a panel of histone deacetylase (HDAC) inhibitors. (4587)

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