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Bump and Hole approach to elucidate function of individual bromodomains of BET proteins

Total Cost €


EC-Contrib. €






Project "Bump-BET" data sheet

The following table provides information about the project.


Organization address
address: Nethergate
city: DUNDEE
postcode: DD1 4HN

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country United Kingdom [UK]
 Project website
 Total cost 183˙454 €
 EC max contribution 183˙454 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2014
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2015
 Duration (year-month-day) from 2015-10-01   to  2017-09-30


Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNIVERSITY OF DUNDEE UK (DUNDEE) coordinator 183˙454.00


 Project objective

Small molecules can be used to probe for biological function of individual proteins. Achieving high selectivity with small molecules against structurally similar paralogues is a challenging task that makes it difficult to characterize function of individual member in the same protein family or individual domain in protein containing multiple target domains. The Bromo and Extra-Terminal (BET) proteins play important roles in transcriptional regulation by controlling networks of genes involved in cellular proliferation and cell cycle regulation. Key to the functions of BET proteins is a pair of highly homologous bromodomains (BD) in tandem, which bind and recognize histone acetylation on its tail. Elucidation of the process controlled by BET proteins would benefit greatly from chemical probes that perturb individual BD with high selectivity. Development of small molecules, including clinical candidate drug I-BET, builds a foundation for us to utilize this chemical probe approach, however lack of selectivity of I-BET against individual BD renders it inapplicable to serve as a chemical probe for individual protein or domain. Recently, we had demonstrated the feasibility of a “bump-and-hole” approach to engineer BD of BET proteins and I-BET molecule to achieve high selectivity. Here we propose to enhance the selectivity of BD and I-BET derivative pair to apply this technology and to probe for the function of individual BD in a cell-based model. Interaction between modified I-BET and selected BD variant, which retain its histone binding functionality, will be further optimized to achieve >100 fold selectivity against all wildtype BD. After that, a cell-based model will be built to substitute endogenous BET protein with exogenous BET containing BD variant. The ultimate goal is to develop a general chemical biology tool to elucidate the role of any individual BD-containing proteins by targeting specifically the engineered BD without affecting any other BD.


year authors and title journal last update
List of publications.
2018 A. C. Runcie, M. Zengerle, K.-H. Chan, A. Testa, L. van Beurden, M. G. J. Baud, O. Epemolu, L. C. J. Ellis, K. D. Read, V. Coulthard, A. Brien, A. Ciulli
Optimization of a “bump-and-hole” approach to allele-selective BET bromodomain inhibition
published pages: 2452-2468, ISSN: 2041-6520, DOI: 10.1039/C7SC02536J
Chemical Science 9/9 2019-07-23
2016 Andrew C Runcie, Kwok-Ho Chan, Michael Zengerle, Alessio Ciulli
Chemical genetics approaches for selective intervention in epigenetics
published pages: 186-194, ISSN: 1367-5931, DOI: 10.1016/j.cbpa.2016.06.031
Current Opinion in Chemical Biology 33 2019-07-23
2017 Kwok-Ho Chan, Michael Zengerle, Andrea Testa, Alessio Ciulli
Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds
published pages: , ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b01912
Journal of Medicinal Chemistry 2019-07-23
2017 Morgan S Gadd, Andrea Testa, Xavier Lucas, Kwok-Ho Chan, Wenzhang Chen, Douglas J Lamont, Michael Zengerle, Alessio Ciulli
Structural basis of PROTAC cooperative recognition for selective protein degradation
published pages: 514-521, ISSN: 1552-4450, DOI: 10.1038/nchembio.2329
Nature Chemical Biology 13/5 2019-07-23

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