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

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

doi:10.1021/acs.jmedchem.1c01747

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

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

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Abstract

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.

Original language	English
Pages (from-to)	2262-2287
Number of pages	26
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	3
Early online date	7 Jan 2022
DOIs	https://doi.org/10.1021/acs.jmedchem.1c01747
Publication status	Published - 10 Feb 2022

Keywords

drug discovery
molecular medicine
bromodomain and extra terminal (BET)
pan-BET inhibitors
I-BET567 (27)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.jmedchem.1c01747

Humphreys-etal-JMC-2022-Design-synthesis-and-characterization-of-I-BET567-a-pan-bromodomain-and-extra-terminal-BET-bromodomainAccepted author manuscript, 2.95 MBLicence: Strath_1

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Humphreys, P. G., Atkinson, S. J., Bamborough, P., Bit, R. A., Chung, C., Craggs, P. D., Cutler, L., Davis, R., Ferrie, A., Gong, G., Gordon, L. J., Gray, M., Harrison, L. A., Hayhow, T. G., Haynes, A., Henley, N., Hirst, D. J., Holyer, I. D., Lindon, M. J., ... Prinjha, R. 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), 2262-2287. https://doi.org/10.1021/acs.jmedchem.1c01747

@article{e1aea61f5a9d4bd58c5e90d98e9d6708,

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

abstract = "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.",

keywords = "drug discovery, molecular medicine, bromodomain and extra terminal (BET), pan-BET inhibitors, I-BET567 (27)",

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

year = "2022",

month = feb,

day = "10",

doi = "10.1021/acs.jmedchem.1c01747",

language = "English",

volume = "65",

pages = "2262--2287",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "3",

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Humphreys, PG, Atkinson, SJ, Bamborough, P, Bit, RA, Chung, C, Craggs, PD, Cutler, L, Davis, R, Ferrie, A, Gong, G, Gordon, LJ, Gray, M, Harrison, LA, Hayhow, TG, Haynes, A, Henley, N, Hirst, DJ, Holyer, ID, Lindon, MJ, Lovatt, C, Lugo, D, McCleary, S, Molnar, J, Osmani, Q, Patten, C, Preston, A, Rioja, I, Seal, JT, Smithers, N, Sun, F, Tang, D, Taylor, S, Theodoulou, NH, Thomas, C, Watson, RJ, Wellaway, CR, Zhu, L, Tomkinson, NCO & Prinjha, RK 2022, 'Design, synthesis, and characterization of I-BET567, a pan-bromodomain and extra terminal (BET) bromodomain oral candidate', Journal of Medicinal Chemistry, vol. 65, no. 3, pp. 2262-2287. https://doi.org/10.1021/acs.jmedchem.1c01747

TY - JOUR

T1 - Design, synthesis, and characterization of I-BET567, a pan-bromodomain and extra terminal (BET) bromodomain oral candidate

AU - Humphreys, Philip G.

AU - Atkinson, Stephen J.

AU - Bamborough, Paul

AU - Bit, Rino A.

AU - Chung, Chun-wa

AU - Craggs, Peter D.

AU - Cutler, Leanne

AU - Davis, Rob

AU - Ferrie, Alan

AU - Gong, GangLi

AU - Gordon, Laurie J.

AU - Gray, Matthew

AU - Harrison, Lee A.

AU - Hayhow, Thomas G.

AU - Haynes, Andrea

AU - Henley, Nick

AU - Hirst, David J.

AU - Holyer, Ian D.

AU - Lindon, Matthew J.

AU - Lovatt, Cerys

AU - Lugo, David

AU - McCleary, Scott

AU - Molnar, Judit

AU - Osmani, Qendresa

AU - Patten, Chris

AU - Preston, Alex

AU - Rioja, Inmaculada

AU - Seal, Jonathan T.

AU - Smithers, Nicholas

AU - Sun, Fenglai

AU - Tang, Dalin

AU - Taylor, Simon

AU - Theodoulou, Natalie H.

AU - Thomas, Clare

AU - Watson, Robert J.

AU - Wellaway, Christopher R.

AU - Zhu, Linrong

AU - Tomkinson, Nicholas C. O.

AU - Prinjha, Rab K.

PY - 2022/2/10

Y1 - 2022/2/10

N2 - 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.

AB - 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.

KW - drug discovery

KW - molecular medicine

KW - bromodomain and extra terminal (BET)

KW - pan-BET inhibitors

KW - I-BET567 (27)

U2 - 10.1021/acs.jmedchem.1c01747

DO - 10.1021/acs.jmedchem.1c01747

M3 - Article

SN - 0022-2623

VL - 65

SP - 2262

EP - 2287

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

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