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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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Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response.pdf | Published version | 1.82 MB | Adobe PDF | View/Open |
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