A new class of α-ketoamide derivatives with potent anticancer and anti-SARS-CoV-2 activities

Eur J Med Chem. 2021 Apr 5:215:113267. doi: 10.1016/j.ejmech.2021.113267.

Juan Wang ¹, Boqiang Liang ², Yiling Chen ², Jasper Fuk-Woo Chan ³, Shuofeng Yuan ³, Hui Ye ², Linlin Nie ², Jiao Zhou ⁴, Yi Wu ², Meixian Wu ⁵, Lina S Huang ⁵, Jing An ⁵, Arieh Warshel ⁶, Kwok-Yung Yuen ³, Aaron Ciechanover ⁷, Ziwei Huang ⁸, Yan Xu ⁹

Affiliations

1 School of Life Sciences, Tsinghua University, Beijing, 100084, China.
2 Nobel Institute of Biomedicine, Zhuhai, 519000, China.
3 State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
4 Nobel Institute of Biomedicine, Zhuhai, 519000, China; Ciechanover Institute of Precision and Regenerative Medicine, School of Life and Health Sciences, Chinese University of Hong Kong, Shenzhen, 518172, China.
5 Department of Medicine, Division of Infectious Diseases and Global Public Health, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA.
6 Department of Chemistry, University of Southern California, Los Angeles, CA, 90089, USA.
7 Nobel Institute of Biomedicine, Zhuhai, 519000, China; Technion-Israel Institute of Technology, Haifa, 3109601, Israel.
8 School of Life Sciences, Tsinghua University, Beijing, 100084, China; Department of Medicine, Division of Infectious Diseases and Global Public Health, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA; Ciechanover Institute of Precision and Regenerative Medicine, School of Life and Health Sciences, Chinese University of Hong Kong, Shenzhen, 518172, China. Electronic address: [email protected].
9 Nobel Institute of Biomedicine, Zhuhai, 519000, China; Ciechanover Institute of Precision and Regenerative Medicine, School of Life and Health Sciences, Chinese University of Hong Kong, Shenzhen, 518172, China. Electronic address: [email protected].

PMID: 33639344 DOI: 10.1016/j.ejmech.2021.113267

Abstract

Inhibitors of the Proteasome have been extensively studied for their applications in the treatment of human diseases such as hematologic malignancies, autoimmune disorders, and viral infections. Many of the Proteasome inhibitors reported in the literature target the non-primed site of proteasome's substrate binding pocket. In this study, we designed, synthesized and characterized a series of novel α-keto phenylamide derivatives aimed at both the primed and non-primed sites of the Proteasome. In these derivatives, different substituted phenyl groups at the head group targeting the primed site were incorporated in order to investigate their structure-activity relationship and optimize the potency of α-keto phenylamides. In addition, the biological effects of modifications at the cap moiety, P1, P2 and P3 side chain positions were explored. Many derivatives displayed highly potent biological activities in Proteasome inhibition and Anticancer activity against a panel of six Cancer cell lines, which were further rationalized by molecular modeling analyses. Furthermore, a representative α-ketoamide derivative was tested and found to be active in inhibiting the cellular Infection of SARS-CoV-2 which causes the COVID-19 pandemic. These results demonstrate that this new class of α-ketoamide derivatives are potent Anticancer agents and provide experimental evidence of the anti-SARS-CoV-2 effect by one of them, thus suggesting a possible new lead to develop Antiviral therapeutics for COVID-19.

Keywords

COVID-19; Cancer; Drug discovery; Proteasome; SARS-CoV-2; α-ketoamides.

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