TY - JOUR
T1 - Discovery of EGT710, an Oral Nonpeptidomimetic Reversible Covalent SARS-CoV-2 Main Protease Inhibitor
AU - Papillon, Julien P.N.
AU - Yuan, Jun
AU - Hesse, Matthew J.
AU - Zhang, Lei
AU - Robinson, Richard I.
AU - Ware, Nathaniel F.
AU - Hornak, Viktor
AU - Karki, Rajeshri G.
AU - Kirrane, Tom
AU - Garland, Keira
AU - Joseph, Sajan
AU - Moquin, Stephanie A.
AU - Lakshminarayana, Suresh B.
AU - Tandeske, Laura
AU - Dovala, Dustin
AU - Knapp, Mark
AU - Ornelas, Elizabeth
AU - Fuller, Daniel
AU - Ho, Pei i.
AU - Xie, Xuping
AU - Vulic, Katarina
AU - Skolnik, Suzanne M.
AU - Gao, Jinhai
AU - Zambrowski, Mark
AU - Spiess, Meike
AU - Duca, José S.
AU - Busby, Scott A.
AU - Schirle, Markus
AU - Robinson, Michael
AU - Shi, Pei Yong
AU - Moser, Heinz E.
AU - Sarko, Christopher
AU - Bradner, James E.
AU - Diagana, Thierry T.
AU - Tallarico, John A.
N1 - Publisher Copyright:
© 2026 The Authors. Published by American Chemical Society
PY - 2026/2/26
Y1 - 2026/2/26
N2 - The coronavirus main protease (3CLpro, Mpro, 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 Mpro 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(1H,3H)-dione and oxoimidazolidine-4-carbonitrile compounds with potent inhibition of SARS-CoV-2 Mpro 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 EGT710. EGT710 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.
AB - The coronavirus main protease (3CLpro, Mpro, 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 Mpro 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(1H,3H)-dione and oxoimidazolidine-4-carbonitrile compounds with potent inhibition of SARS-CoV-2 Mpro 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 EGT710. EGT710 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.
UR - https://www.scopus.com/pages/publications/105031259228
UR - https://www.scopus.com/pages/publications/105031259228#tab=citedBy
U2 - 10.1021/acs.jmedchem.5c02360
DO - 10.1021/acs.jmedchem.5c02360
M3 - Article
C2 - 41663073
AN - SCOPUS:105031259228
SN - 0022-2623
VL - 69
SP - 3868
EP - 3886
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 4
ER -