Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/35805
Title: Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response
Authors: WILSON, David 
Deacon, AM
Duncton, MAJ
Pellicena, P
Georgiadis, MM
Yeh, AP
Arvai, AS
Moiani, D
Tainer, JA
Das , D
Issue Date: 2021
Publisher: PERGAMON-ELSEVIER SCIENCE LTD
Source: Progress in Biophysics and Molecular Biology, 163 , p. 130 -142
Abstract: Cancer will directly affect the lives of over one-third of the population. The DNA Damage Response (DDR) is an intricate system involving damage recognition, cell cycle regulation, DNA repair, and ultimately cell fate determination, playing a central role in cancer etiology and therapy. Two primary therapeutic approaches involving DDR targeting include: combinatorial treatments employing anticancer genotoxic agents; and synthetic lethality, exploiting a sporadic DDR defect as a mechanism for cancer-specific therapy. Whereas, many DDR proteins have proven "undruggable", Fragment- and Structure-Based Drug Discovery (FBDD, SBDD) have advanced therapeutic agent identification and development. FBDD has led to 4 (with -50 more drugs under preclinical and clinical development), while SBDD is estimated to have contributed to the development of >200, FDA-approved medicines. Protein X-ray crystallography-based fragment library screening, especially for elusive or "undruggable" targets, allows for simultaneous generation of hits plus details of protein-ligand interactions and binding sites (orthosteric or allosteric) that inform chemical tractability, downstream biology, and intellectual property. Using a novel high-throughput crystallography-based fragment library screening platform, we screened five diverse proteins, yielding hit rates of -2-8% and crystal structures from -1.8 to 3.2 & Aring;. We consider current FBDD/SBDD methods and some exemplary results of efforts to design inhibitors against the DDR nucleases meiotic recombination 11 (MRE11, a.k.a., MRE11A), apurinic/apyrimidinic endonuclease 1 (APE1, a.k.a., APEX1), and flap endonuclease 1 (FEN1).(c) 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
Keywords: Fragment-based drug discovery;Structure-based drug discovery;X-ray crystallography;Cancer therapeutics;DNA damage Response;DNA repair;MRE11;APE1;FEN1
Document URI: http://hdl.handle.net/1942/35805
ISSN: 0079-6107
e-ISSN: 1873-1732
DOI: 10.1016/j.pbiomolbio.2020.10.005
ISI #: 000658757700012
Rights: 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Category: A1
Type: Journal Contribution
Validations: ecoom 2022
Appears in Collections:Research publications

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