Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Covalent Warhead

Elshan, N. G. R. D.; Wolff, K. C.; Riva, L.; Woods, A. K.; Grabovyi, G.; Wilson, K.; Rahimi, A.; Pedroarena, J.; Ghorai, S.; Gupta, A. K.; Nazarian, A.; Weiss, F.; Liu, Y.; Mazumdar, W.; Song, L.; Okwor, N.; Malvin, J.; Bakowski, M. A.; Beutler, N.; Kirkpatrick, M. G.; Gebara-Lamb, A.; Huang, E.; Nguyen-Tran, V.; Chi, V.; Li, S.; Rogers, T. F.; McNamara, C. W.; Chen, J. J.; Joseph, S. B.; Schultz, P. G.; Chatterjee, A. K.

doi:10.1101/2023.10.24.563688

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bioRxiv · 10.1101/2023.10.24.563688

Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Covalent Warhead

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Abstract

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof towards human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = PaxlovidTM), CMX990 has distinctly differentiated potency ([~]5x more potent in primary cells) and human in vitro clearance (>4x better microsomal clearance and >10x better hepatocyte clearance), with good in vitro-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.

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Elshan, N. G. R. D., Wolff, K. C., Riva, L., Woods, A. K., Grabovyi, G., Wilson, K., Rahimi, A., Pedroarena, J., Ghorai, S., Gupta, A. K., Nazarian, A., Weiss, F., Liu, Y., Mazumdar, W., Song, L., Okwor, N., Malvin, J., Bakowski, M. A., Beutler, N., Kirkpatrick, M. G., Gebara-Lamb, A., Huang, E., Nguyen-Tran, V., Chi, V., Li, S., Rogers, T. F., McNamara, C. W., Chen, J. J., Joseph, S. B., Schultz, P. G., Chatterjee, A. K.. 2023-10-25. Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Covalent Warhead. https://doi.org/10.1101/2023.10.24.563688

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