Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain

Michael Brand; James Clayton; Mustafa Moroglu; Matthias Schiedel; Sarah Picaud; Joseph P. Bluck; Anna Skwarska; Hannah Bolland; Anthony K.N. Chan; Corentine M.C. Laurin; Amy R. Scorah; Larissa See; Timothy P.C. Rooney; Katrina H. Andrews; Oleg Fedorov; Gabriella Perell; Prakriti Kalra; Kayla B. Vinh; Wilian A. Cortopassi; Pascal Heitel; Kirsten E. Christensen; Richard I. Cooper; Robert S. Paton; William C.K. Pomerantz; Philip C. Biggin; Ester M. Hammond; Panagis Filippakopoulos; Stuart J. Conway

doi:10.1021/acs.jmedchem.1c00348

Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain

Michael Brand, James Clayton, Mustafa Moroglu, Matthias Schiedel, Sarah Picaud, Joseph P. Bluck, Anna Skwarska, Hannah Bolland, Anthony K.N. Chan, Corentine M.C. Laurin, Amy R. Scorah, Larissa See, Timothy P.C. Rooney, Katrina H. Andrews, Oleg Fedorov, Gabriella Perell, Prakriti Kalra, Kayla B. Vinh, Wilian A. Cortopassi, Pascal HeitelKirsten E. Christensen, Richard I. Cooper, Robert S. Paton, William C.K. Pomerantz, Philip C. Biggin, Ester M. Hammond, Panagis Filippakopoulos, Stuart J. Conway

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. In hypoxia (<0.1% O 2), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α.

Original language	English (US)
Pages (from-to)	10102-10123
Number of pages	22
Journal	Journal of medicinal chemistry
Volume	64
Issue number	14
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00348
State	Published - Jul 22 2021

Bibliographical note

Funding Information:
M.B. thanks Lincoln College, Oxford, for the provision of a Berrow Foundation Scholarship. M.M. and A.R.S. thank the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) and AstraZeneca, Diamond Light Source, Defense Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex for studentship support. M.S. and P. H. were supported by the Deutsche Forschungsgemeinschaft (SCHI 1408/1-1 and HE 8639/1-1). J.B. and T.P.C.R. were supported by the EPSRC and the MRC through the Systems Approaches to Biomedical Sciences Doctoral Training Centre (EP/G037280/1) with additional support from GlaxoSmithKline for J. B. and Pfizer Neusentis for T.P.C.R. This project (J.C. and A.K.N.C.) has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement nos. 658825 and 660156. C.M.C.L. and K.H.A. thank the BBSRC and GlaxoSmithKline for studentship support (BB/M015157/1 and BB/S507003/1). W.A.C. was supported by a Science Without Borders (CAPES) scholarship. A.S., E.M.H., and S.J.C. thank the Medical Research Council (MR/N009460/1) for the award of a project grant. H.B., E.M.H., and S.J.C. thank the EPSRC for the award of a programme grant (EP/S019901/1). W.C.K.P. was supported by the National Science Foundation (CHE-1352091, CHE-1904071). P.F. thanks the Wellcome Trust (095751/Z/11/Z) and Medical Research Council (MR/N010051/1). P.C.B. thanks Lady Margaret Hall, Oxford, for research funding. S.J.C. thanks St Hugh’s College, Oxford, for research funding.

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© 2021 The Authors. Published by American Chemical Society

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Brand, M., Clayton, J., Moroglu, M., Schiedel, M., Picaud, S., Bluck, J. P., Skwarska, A., Bolland, H., Chan, A. K. N., Laurin, C. M. C., Scorah, A. R., See, L., Rooney, T. P. C., Andrews, K. H., Fedorov, O., Perell, G., Kalra, P., Vinh, K. B., Cortopassi, W. A., ... Conway, S. J. (2021). Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain. Journal of medicinal chemistry, 64(14), 10102-10123. https://doi.org/10.1021/acs.jmedchem.1c00348

Brand, M, Clayton, J, Moroglu, M, Schiedel, M, Picaud, S, Bluck, JP, Skwarska, A, Bolland, H, Chan, AKN, Laurin, CMC, Scorah, AR, See, L, Rooney, TPC, Andrews, KH, Fedorov, O, Perell, G, Kalra, P, Vinh, KB, Cortopassi, WA, Heitel, P, Christensen, KE, Cooper, RI, Paton, RS, Pomerantz, WCK, Biggin, PC, Hammond, EM, Filippakopoulos, P & Conway, SJ 2021, 'Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain', Journal of medicinal chemistry, vol. 64, no. 14, pp. 10102-10123. https://doi.org/10.1021/acs.jmedchem.1c00348

@article{27c8615d53204402803799c48357ffba,

title = "Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain",

abstract = "CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. In hypoxia (<0.1% O 2), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α. ",

author = "Michael Brand and James Clayton and Mustafa Moroglu and Matthias Schiedel and Sarah Picaud and Bluck, {Joseph P.} and Anna Skwarska and Hannah Bolland and Chan, {Anthony K.N.} and Laurin, {Corentine M.C.} and Scorah, {Amy R.} and Larissa See and Rooney, {Timothy P.C.} and Andrews, {Katrina H.} and Oleg Fedorov and Gabriella Perell and Prakriti Kalra and Vinh, {Kayla B.} and Cortopassi, {Wilian A.} and Pascal Heitel and Christensen, {Kirsten E.} and Cooper, {Richard I.} and Paton, {Robert S.} and Pomerantz, {William C.K.} and Biggin, {Philip C.} and Hammond, {Ester M.} and Panagis Filippakopoulos and Conway, {Stuart J.}",

note = "Funding Information: M.B. thanks Lincoln College, Oxford, for the provision of a Berrow Foundation Scholarship. M.M. and A.R.S. thank the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) and AstraZeneca, Diamond Light Source, Defense Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex for studentship support. M.S. and P. H. were supported by the Deutsche Forschungsgemeinschaft (SCHI 1408/1-1 and HE 8639/1-1). J.B. and T.P.C.R. were supported by the EPSRC and the MRC through the Systems Approaches to Biomedical Sciences Doctoral Training Centre (EP/G037280/1) with additional support from GlaxoSmithKline for J. B. and Pfizer Neusentis for T.P.C.R. This project (J.C. and A.K.N.C.) has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement nos. 658825 and 660156. C.M.C.L. and K.H.A. thank the BBSRC and GlaxoSmithKline for studentship support (BB/M015157/1 and BB/S507003/1). W.A.C. was supported by a Science Without Borders (CAPES) scholarship. A.S., E.M.H., and S.J.C. thank the Medical Research Council (MR/N009460/1) for the award of a project grant. H.B., E.M.H., and S.J.C. thank the EPSRC for the award of a programme grant (EP/S019901/1). W.C.K.P. was supported by the National Science Foundation (CHE-1352091, CHE-1904071). P.F. thanks the Wellcome Trust (095751/Z/11/Z) and Medical Research Council (MR/N010051/1). P.C.B. thanks Lady Margaret Hall, Oxford, for research funding. S.J.C. thanks St Hugh{\textquoteright}s College, Oxford, for research funding. Publisher Copyright: {\textcopyright} 2021 The Authors. Published by American Chemical Society",

year = "2021",

month = jul,

day = "22",

doi = "10.1021/acs.jmedchem.1c00348",

language = "English (US)",

volume = "64",

pages = "10102--10123",

journal = "Journal of medicinal chemistry",

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TY - JOUR

T1 - Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain

AU - Brand, Michael

AU - Clayton, James

AU - Moroglu, Mustafa

AU - Schiedel, Matthias

AU - Picaud, Sarah

AU - Bluck, Joseph P.

AU - Skwarska, Anna

AU - Bolland, Hannah

AU - Chan, Anthony K.N.

AU - Laurin, Corentine M.C.

AU - Scorah, Amy R.

AU - See, Larissa

AU - Rooney, Timothy P.C.

AU - Andrews, Katrina H.

AU - Fedorov, Oleg

AU - Perell, Gabriella

AU - Kalra, Prakriti

AU - Vinh, Kayla B.

AU - Cortopassi, Wilian A.

AU - Heitel, Pascal

AU - Christensen, Kirsten E.

AU - Cooper, Richard I.

AU - Paton, Robert S.

AU - Pomerantz, William C.K.

AU - Biggin, Philip C.

AU - Hammond, Ester M.

AU - Filippakopoulos, Panagis

AU - Conway, Stuart J.

N1 - Funding Information: M.B. thanks Lincoln College, Oxford, for the provision of a Berrow Foundation Scholarship. M.M. and A.R.S. thank the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) and AstraZeneca, Diamond Light Source, Defense Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex for studentship support. M.S. and P. H. were supported by the Deutsche Forschungsgemeinschaft (SCHI 1408/1-1 and HE 8639/1-1). J.B. and T.P.C.R. were supported by the EPSRC and the MRC through the Systems Approaches to Biomedical Sciences Doctoral Training Centre (EP/G037280/1) with additional support from GlaxoSmithKline for J. B. and Pfizer Neusentis for T.P.C.R. This project (J.C. and A.K.N.C.) has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement nos. 658825 and 660156. C.M.C.L. and K.H.A. thank the BBSRC and GlaxoSmithKline for studentship support (BB/M015157/1 and BB/S507003/1). W.A.C. was supported by a Science Without Borders (CAPES) scholarship. A.S., E.M.H., and S.J.C. thank the Medical Research Council (MR/N009460/1) for the award of a project grant. H.B., E.M.H., and S.J.C. thank the EPSRC for the award of a programme grant (EP/S019901/1). W.C.K.P. was supported by the National Science Foundation (CHE-1352091, CHE-1904071). P.F. thanks the Wellcome Trust (095751/Z/11/Z) and Medical Research Council (MR/N010051/1). P.C.B. thanks Lady Margaret Hall, Oxford, for research funding. S.J.C. thanks St Hugh’s College, Oxford, for research funding. Publisher Copyright: © 2021 The Authors. Published by American Chemical Society

PY - 2021/7/22

Y1 - 2021/7/22

N2 - CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. In hypoxia (<0.1% O 2), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α.

AB - CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. In hypoxia (<0.1% O 2), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α.

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Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain

Abstract

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