A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1
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 si...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/23/16637 |
| _version_ | 1797400111016312832 |
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| author | Debanu Das Matthew A. J. Duncton Taxiarchis M. Georgiadis Patricia Pellicena Jennifer Clark Robert W. Sobol Millie M. Georgiadis John King-Underwood David V. Jobes Caleb Chang Yang Gao Ashley M. Deacon David M. Wilson |
| author_facet | Debanu Das Matthew A. J. Duncton Taxiarchis M. Georgiadis Patricia Pellicena Jennifer Clark Robert W. Sobol Millie M. Georgiadis John King-Underwood David V. Jobes Caleb Chang Yang Gao Ashley M. Deacon David M. Wilson |
| author_sort | Debanu Das |
| collection | DOAJ |
| description | 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 SaXPy<sup>TM</sup> (“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 η 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. |
| first_indexed | 2024-03-09T01:50:49Z |
| format | Article |
| id | doaj.art-714dd19a534f4a5790f6074294d7ca26 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T01:50:49Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-714dd19a534f4a5790f6074294d7ca262023-12-08T15:16:36ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124231663710.3390/ijms242316637A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1Debanu Das0Matthew A. J. Duncton1Taxiarchis M. Georgiadis2Patricia Pellicena3Jennifer Clark4Robert W. Sobol5Millie M. Georgiadis6John King-Underwood7David V. Jobes8Caleb Chang9Yang Gao10Ashley M. Deacon11David M. Wilson12XPose Therapeutics, Inc., San Carlos, CA 94070, USAXPose Therapeutics, Inc., San Carlos, CA 94070, USAXPose Therapeutics, Inc., San Carlos, CA 94070, USAXPose Therapeutics, Inc., San Carlos, CA 94070, USAMitchell Cancer Institute and Department of Pharmacology, University of South Alabama, Mobile, AL 36604, USAMitchell Cancer Institute and Department of Pharmacology, University of South Alabama, Mobile, AL 36604, USAXPose Therapeutics, Inc., San Carlos, CA 94070, USAXPose Therapeutics, Inc., San Carlos, CA 94070, USAXPose Therapeutics, Inc., San Carlos, CA 94070, USADepartment of BioSciences, Rice University, Houston, TX 77251, USADepartment of BioSciences, Rice University, Houston, TX 77251, USAXPose Therapeutics, Inc., San Carlos, CA 94070, USAXPose Therapeutics, Inc., San Carlos, CA 94070, USAThe 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 SaXPy<sup>TM</sup> (“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 η 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.https://www.mdpi.com/1422-0067/24/23/16637fragment-based drug discoverystructure-based drug discoveryX-ray crystallographycancer therapeuticsDNA damage responsepolymerases |
| spellingShingle | Debanu Das Matthew A. J. Duncton Taxiarchis M. Georgiadis Patricia Pellicena Jennifer Clark Robert W. Sobol Millie M. Georgiadis John King-Underwood David V. Jobes Caleb Chang Yang Gao Ashley M. Deacon David M. Wilson A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1 International Journal of Molecular Sciences fragment-based drug discovery structure-based drug discovery X-ray crystallography cancer therapeutics DNA damage response polymerases |
| title | A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1 |
| title_full | A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1 |
| title_fullStr | A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1 |
| title_full_unstemmed | A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1 |
| title_short | A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1 |
| title_sort | new drug discovery platform application to dna polymerase eta and apurinic apyrimidinic endonuclease 1 |
| topic | fragment-based drug discovery structure-based drug discovery X-ray crystallography cancer therapeutics DNA damage response polymerases |
| url | https://www.mdpi.com/1422-0067/24/23/16637 |
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