A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes

Matthias G. J. Baud; Enrique Lin-Shiao; Teresa Cardote; Cynthia Tallant; Annica Pschibul; Kwok-Ho Chan; Michael Zengerle; Jordi R. Garcia; Terence T.-L. Kwan; Fleur M. Ferguson; Alessio Ciulli

doi:10.1126/science.1249830

A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes

Matthias G. J. Baud, Enrique Lin-Shiao, Teresa Cardote, Cynthia Tallant, Annica Pschibul, Kwok-Ho Chan, Michael Zengerle, Jordi R. Garcia, Terence T.-L. Kwan, Fleur M. Ferguson, Alessio Ciulli (Lead / Corresponding author)

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

121 Citations (Scopus)

Abstract

Small molecules are useful tools for probing the biological function and therapeutic potential of individual proteins, but achieving selectivity is challenging when the target protein shares structural domains with other proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest because of their roles in transcriptional regulation, epigenetics, and cancer. The BET bromodomains (protein interaction modules that bind acetyl-lysine) have been targeted by potent small-molecule inhibitors but these inhibitors lack selectivity for individual family members. We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET, and showed that it binds Leu/Ala mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BET protein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BET proteins in human physiology and disease.

Original language	English
Pages (from-to)	638-641
Number of pages	4
Journal	Science
Volume	346
Issue number	6209
DOIs	https://doi.org/10.1126/science.1249830
Publication status	Published - 31 Oct 2014

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10.1126/science.1249830

A Systems Approach for the Fragment-based Development of Selective Chemical Probes of Bromodomain Function (joint with University of Oxford)
Ciulli, A. (Investigator)
Biotechnology and Biological Sciences Research Council
8/04/13 → 7/06/15
Project: Research
Dissecting and Exploiting Molecular Recognition at Protein-Protein Interfaces (David Phillips Fellowship)
Ciulli, A. (Investigator)
Biotechnology and Biological Sciences Research Council
8/04/13 → 7/07/15
Project: Research

Ciulli, Alessio
- Centre for Targeted Protein Degradation - Professor of Chemical and Structural Biology
Person: Academic

Cite this

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title = "A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes",

abstract = "Small molecules are useful tools for probing the biological function and therapeutic potential of individual proteins, but achieving selectivity is challenging when the target protein shares structural domains with other proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest because of their roles in transcriptional regulation, epigenetics, and cancer. The BET bromodomains (protein interaction modules that bind acetyl-lysine) have been targeted by potent small-molecule inhibitors but these inhibitors lack selectivity for individual family members. We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET, and showed that it binds Leu/Ala mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BET protein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BET proteins in human physiology and disease.",

author = "Baud, {Matthias G. J.} and Enrique Lin-Shiao and Teresa Cardote and Cynthia Tallant and Annica Pschibul and Kwok-Ho Chan and Michael Zengerle and Garcia, {Jordi R.} and Kwan, {Terence T.-L.} and Ferguson, {Fleur M.} and Alessio Ciulli",

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doi = "10.1126/science.1249830",

language = "English",

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T1 - A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes

AU - Baud, Matthias G. J.

AU - Lin-Shiao, Enrique

AU - Cardote, Teresa

AU - Tallant, Cynthia

AU - Pschibul, Annica

AU - Chan, Kwok-Ho

AU - Zengerle, Michael

AU - Garcia, Jordi R.

AU - Kwan, Terence T.-L.

AU - Ferguson, Fleur M.

AU - Ciulli, Alessio

PY - 2014/10/31

Y1 - 2014/10/31

N2 - Small molecules are useful tools for probing the biological function and therapeutic potential of individual proteins, but achieving selectivity is challenging when the target protein shares structural domains with other proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest because of their roles in transcriptional regulation, epigenetics, and cancer. The BET bromodomains (protein interaction modules that bind acetyl-lysine) have been targeted by potent small-molecule inhibitors but these inhibitors lack selectivity for individual family members. We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET, and showed that it binds Leu/Ala mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BET protein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BET proteins in human physiology and disease.

AB - Small molecules are useful tools for probing the biological function and therapeutic potential of individual proteins, but achieving selectivity is challenging when the target protein shares structural domains with other proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest because of their roles in transcriptional regulation, epigenetics, and cancer. The BET bromodomains (protein interaction modules that bind acetyl-lysine) have been targeted by potent small-molecule inhibitors but these inhibitors lack selectivity for individual family members. We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET, and showed that it binds Leu/Ala mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BET protein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BET proteins in human physiology and disease.

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DO - 10.1126/science.1249830

M3 - Article

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SN - 0036-8075

VL - 346

SP - 638

EP - 641

JO - Science

JF - Science

IS - 6209

ER -

A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes

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Projects

A Systems Approach for the Fragment-based Development of Selective Chemical Probes of Bromodomain Function (joint with University of Oxford)

Dissecting and Exploiting Molecular Recognition at Protein-Protein Interfaces (David Phillips Fellowship)

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Ciulli, Alessio

Cite this