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Title: | A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1 | Authors: | Das, Debanu Duncton, Matthew A. J. Georgiadis, Taxiarchis M. Pellicena, Patricia Clark, Jennifer Sobol, Robert W. Georgiadis, Millie M. King-Underwood, John Jobes, David V. Chang, Caleb Gao, Yang Deacon, Ashley M. WILSON, David |
Issue Date: | 2023 | Publisher: | MDPI | Source: | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 24 (23) (Art N° 16637) | Abstract: | The ability to quickly discover reliable hits from screening and rapidly convert them into lead compounds, which can be verified in functional assays, is central to drug discovery. The expedited validation of novel targets and the identification of modulators to advance to preclinical studies can significantly increase drug development success. Our SaXPyTM ("SAR by X-ray Poses Quickly") platform, which is applicable to any X-ray crystallography-enabled drug target, couples the established methods of protein X-ray crystallography and fragment-based drug discovery (FBDD) with advanced computational and medicinal chemistry to deliver small molecule modulators or targeted protein degradation ligands in a short timeframe. Our approach, especially for elusive or "undruggable" targets, allows for (i) hit generation; (ii) the mapping of protein-ligand interactions; (iii) the assessment of target ligandability; (iv) the discovery of novel and potential allosteric binding sites; and (v) hit-to-lead execution. These advances inform chemical tractability and downstream biology and generate novel intellectual property. We describe here the application of SaXPy in the discovery and development of DNA damage response inhibitors against DNA polymerase eta (Pol eta or POLH) and apurinic/apyrimidinic endonuclease 1 (APE1 or APEX1). Notably, our SaXPy platform allowed us to solve the first crystal structures of these proteins bound to small molecules and to discover novel binding sites for each target. | Notes: | Das, D (corresponding author), XPose Therapeut Inc, San Carlos, CA 94070 USA.; Das, D (corresponding author), Accelero Biostruct Inc, San Carlos, CA 94070 USA. info@xposetx.com |
Keywords: | fragment-based drug discovery;structure-based drug discovery;X-ray crystallography;cancer therapeutics;DNA damage response;polymerases;Pol eta;POLH;APE1;targeted protein degradation;synthetic lethality | Document URI: | http://hdl.handle.net/1942/42024 | ISSN: | 1661-6596 | e-ISSN: | 1422-0067 | DOI: | 10.3390/ijms242316637 | ISI #: | 001116016400001 | Rights: | 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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A New Drug Discovery Platform_ Application to DNA Polymerase Eta and Apurinic_Apyrimidinic Endonuclease 1.pdf | Published version | 3.31 MB | Adobe PDF | View/Open |
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