7OE6

Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors.

Seal, J.T., Atkinson, S.J., Bamborough, P., Bassil, A., Chung, C.W., Foley, J., Gordon, L., Grandi, P., Gray, J.R.J., Harrison, L.A., Kruger, R.G., Matteo, J.J., McCabe, M.T., Messenger, C., Mitchell, D., Phillipou, A., Preston, A., Prinjha, R.K., Rianjongdee, F., Rioja, I., Taylor, S., Wall, I.D., Watson, R.J., Woolven, J.M., Wyce, A., Zhang, X.P., Demont, E.H.

(2021) J Med Chem 64: 10772-10805

• PubMed: 34255512 Search on PubMed
• DOI: https://doi.org/10.1021/acs.jmedchem.1c00365
• Primary Citation of Related Structures:  
  7OE4, 7OE5, 7OE6, 7OGY


• PubMed Abstract: 
  

  The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6 . We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.

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Organizational Affiliation: 

Cancer Epigenetics Research Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.