Design, synthesis, and characterization of I-BET567, a pan-bromodomain and extra terminal (BET) bromodomain oral candidate

Humphreys, Philip G. and Atkinson, Stephen J. and Bamborough, Paul and Bit, Rino A. and Chung, Chun-wa and Craggs, Peter D. and Cutler, Leanne and Davis, Rob and Ferrie, Alan and Gong, GangLi and Gordon, Laurie J. and Gray, Matthew and Harrison, Lee A. and Hayhow, Thomas G. and Haynes, Andrea and Henley, Nick and Hirst, David J. and Holyer, Ian D. and Lindon, Matthew J. and Lovatt, Cerys and Lugo, David and McCleary, Scott and Molnar, Judit and Osmani, Qendresa and Patten, Chris and Preston, Alex and Rioja, Inmaculada and Seal, Jonathan T. and Smithers, Nicholas and Sun, Fenglai and Tang, Dalin and Taylor, Simon and Theodoulou, Natalie H. and Thomas, Clare and Watson, Robert J. and Wellaway, Christopher R. and Zhu, Linrong and Tomkinson, Nicholas C. O. and Prinjha, Rab K. (2022) Design, synthesis, and characterization of I-BET567, a pan-bromodomain and extra terminal (BET) bromodomain oral candidate. Journal of Medicinal Chemistry, 65 (3). pp. 2262-2287. ISSN 0022-2623 (

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Through regulation of the epigenome, the bromodomain and extra terminal (BET) family of proteins represent important therapeutic targets for the treatment of human disease. Through mimicking the endogenous N-acetyl-lysine group and disrupting the protein–protein interaction between histone tails and the bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes the medicinal chemistry strategy and execution to deliver an orally bioavailable tetrahydroquinoline (THQ) pan-BET candidate. Critical to the success of this endeavor was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors within the GSK collection which enabled identification of appropriate lipophilicity space to deliver compounds with a higher probability of desired oral candidate quality properties. SAR knowledge was leveraged via Free–Wilson analysis within this design space to identify a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy in mouse models of oncology and inflammation.


Humphreys, Philip G., Atkinson, Stephen J., Bamborough, Paul, Bit, Rino A., Chung, Chun-wa, Craggs, Peter D., Cutler, Leanne, Davis, Rob, Ferrie, Alan, Gong, GangLi, Gordon, Laurie J., Gray, Matthew, Harrison, Lee A., Hayhow, Thomas G., Haynes, Andrea, Henley, Nick, Hirst, David J., Holyer, Ian D., Lindon, Matthew J., Lovatt, Cerys, Lugo, David, McCleary, Scott, Molnar, Judit, Osmani, Qendresa, Patten, Chris, Preston, Alex, Rioja, Inmaculada, Seal, Jonathan T., Smithers, Nicholas, Sun, Fenglai, Tang, Dalin, Taylor, Simon, Theodoulou, Natalie H., Thomas, Clare, Watson, Robert J., Wellaway, Christopher R., Zhu, Linrong, Tomkinson, Nicholas C. O. ORCID logoORCID: and Prinjha, Rab K.;