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Identification of a novel ligand for the ATAD2 bromodomain with selectivity over BRD4 through a fragment growing approach

Lookup NU author(s): Duncan Miller, Dr Mathew Martin, Santosh Adhikari, Alfie Brennan, Professor Jane Endicott, Professor Bernard Golding, Dr Ian Hardcastle, Amy Heptinstall, Dr Stephen Hobson, Dr Claire Jennings, Dr Lauren Molyneux, Professor Steve Wedge, Professor Martin Noble, Dr Celine Cano

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2018 The Royal Society of Chemistry. ATAD2 is an ATPase that is overexpressed in a variety of cancers and associated with a poor patient prognosis. This protein has been suggested to function as a cofactor for a range of transcription factors, including the proto-oncogene MYC and the androgen receptor. ATAD2 comprises an ATPase domain, implicated in chromatin remodelling, and a bromodomain which allows it to interact with acetylated histone tails. Dissection of the functional roles of these two domains would benefit from the availability of selective, cell-permeable pharmacological probes. An in silico evaluation of the 3D structures of various bromodomains suggested that developing small molecule ligands for the bromodomain of ATAD2 is likely to be challenging, although recent reports have shown that ATAD2 bromodomain ligands can be identified. We report a structure-guided fragment-based approach to identify lead compounds for ATAD2 bromodomain inhibitor development. Our findings indicate that the ATAD2 bromodomain can accommodate fragment hits (Mr < 200) that yield productive structure-activity relationships, and structure-guided design enabled the introduction of selectivity over BRD4.


Publication metadata

Author(s): Miller DC, Martin MP, Adhikari S, Brennan A, Endicott JA, Golding BT, Hardcastle IR, Heptinstall A, Hobson S, Jennings C, Molyneux L, Ng Y, Wedge SR, Noble MEM, Cano C

Publication type: Article

Publication status: Published

Journal: Organic and Biomolecular Chemistry

Year: 2018

Volume: 16

Issue: 11

Pages: 1843-1850

Print publication date: 21/03/2018

Online publication date: 15/02/2018

Acceptance date: 15/02/2018

Date deposited: 03/04/2018

ISSN (print): 1477-0520

ISSN (electronic): 1477-0539

Publisher: Royal Society of Chemistry

URL: https://doi.org/10.1039/c8ob00099a

DOI: 10.1039/c8ob00099a


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