Discovery of EGT710, an Oral Nonpeptidomimetic Reversible Covalent SARS-CoV-2 Main Protease Inhibitor
The coronavirus main protease (3CL<sup>pro</sup>, M<sup>pro</sup>, nsp5) is a highly conserved cysteine protease unique to the Coronaviridae family, including SARS-CoV-2, and is a validated target for the treatment of COVID-19. Our efforts focused on the identification of a nonpeptidomimetic M<sup>pro</sup> inhibitor, due to the potential for superior pharmacological properties. Herein, we report our efforts leveraging virtual screening and X-ray crystallography that enabled a structure-based drug design approach, leading to the discovery of series of quinazoline-2,4(1<i>H</i>,3<i>H</i>)-dione and oxoimidazolidine-4-carbonitrile compounds with potent inhibition of SARS-CoV-2 M<sup>pro</sup> as well as other coronaviruses main proteases. Extensive lead optimization focusing on pharmacokinetic properties, developability, and breadth of activity across coronaviruses, led to the identification of <b>EGT710</b>. <b>EGT710</b> demonstrates excellent potency against SARS-CoV-2 infection in a primary differentiated normal human bronchial epithelial (dNHBE) cellular assay, as well as a favorable pharmacology profile that supported advancement into preclinical and clinical studies.
Authors
- José S. Duca (ORCID: https://orcid.org/0000-0002-0880-5618)
- Daniel Fuller (ORCID: https://orcid.org/0000-0002-8896-3746)
- Xuping Xie
- Nathaniel F. Ware (ORCID: https://orcid.org/0009-0002-7038-4786)
- Laura Tandeske
- Keira Garland
- Dustin Dovala (ORCID: https://orcid.org/0000-0002-2278-5027)
- Suresh B. Lakshminarayana (ORCID: https://orcid.org/0000-0002-9133-3147)
- Pei-i Ho
- M. Zambrowski
- Tom Kirrane
- Thierry T. Diagana (ORCID: https://orcid.org/0000-0002-8520-5683)
- Matthew J. Hesse (ORCID: https://orcid.org/0000-0002-4759-5086)
- Richard I. Robinson (ORCID: https://orcid.org/0000-0002-7209-3424)
- Scott A. Busby
- Suzanne Skolnik
- Stephanie Moquin (ORCID: https://orcid.org/0000-0002-8696-4315)
- John A. Tallarico (ORCID: https://orcid.org/0000-0002-8040-8422)
- Heinz E. Moser (ORCID: https://orcid.org/0000-0002-8013-2139)
- Viktor Horn̆ák (ORCID: https://orcid.org/0000-0002-2344-9586)
- Elizabeth Ornelas (ORCID: https://orcid.org/0000-0002-2629-3644)
- Meike Spiess
- Christopher R. Sarko (ORCID: https://orcid.org/0000-0003-0492-908X)
- Jinhai Gao
- Sajan Joseph
- Mark Knapp (ORCID: https://orcid.org/0000-0002-5770-7715)
- James E. Bradner
- Rajeshri G. Karki
- Markus Schirle
- Katarina Vulic
- Lei Zhang
- Michael Robinson
- Jun Yuan
- Julien P. N. Papillon
Institutions
- Novartis (Switzerland) (CH)
- Technical University of Nova Scotia (CA)
- Novartis (China) (CN)
- Health Biomed (China) (CN)
- The University of Texas Medical Branch at Galveston (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-02-09
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02360
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 0.00