SRX3177, a CDK4/6-PI3K-BET inhibitor, in combination with an RdRp inhibitor, Molnupiravir, or an entry inhibitor MU-UNMC-2, has potent antiviral activity against the Omicron variant of SARS-CoV-2

Kabita Pandey; Arpan Acharya; Dhananjaya Pal; Prashant Jain; Kamal Singh; Donald L Durden; Tatiana G Kutateladze; Aniruddha J Deshpande; Siddappa N Byrareddy

doi:10.1016/j.antiviral.2024.105904

SRX3177, a CDK4/6-PI3K-BET inhibitor, in combination with an RdRp inhibitor, Molnupiravir, or an entry inhibitor MU-UNMC-2, has potent antiviral activity against the Omicron variant of SARS-CoV-2

Antiviral Res. 2024 May 8:227:105904. doi: 10.1016/j.antiviral.2024.105904. Online ahead of print.

Authors

Kabita Pandey¹, Arpan Acharya¹, Dhananjaya Pal², Prashant Jain³, Kamal Singh⁴, Donald L Durden², Tatiana G Kutateladze⁵, Aniruddha J Deshpande³, Siddappa N Byrareddy⁶

Affiliations

¹ Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68131, USA.
² Molecular Targeted Therapeutics Laboratory, Levine Cancer Institute, Charlotte, NC, 28204, USA; Division of Hematology and Oncology, Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA.
³ Cancer Genome and Epigenetics Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92127, USA.
⁴ Bond Life Sciences Center, University of Missouri, Columbia, MO, USA; Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA.
⁵ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
⁶ Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68131, USA. Electronic address: sid.byrareddy@unmc.edu.

PMID: 38729306
DOI: 10.1016/j.antiviral.2024.105904

Abstract

Despite considerable progress in developing vaccines and antivirals to combat COVID-19, the rapid mutations of the SARS-CoV-2 genome have limited the durability and efficacy of the current vaccines and therapeutic interventions. Hence, it necessitates the development of novel therapeutic approaches or repurposing existing drugs that target either viral life cycle, host factors, or both. Here, we report that SRX3177, a potent triple-activity CDK4/6-PI3K-BET inhibitor, blocks replication of the SARS-CoV-2 Omicron variant with IC₅₀ values at sub-micromolar concentrations without any impact on the cell proliferation of Calu-3 cells at and below its IC₅₀ concentration. When SRX3177 is combined with EIDD-1931 (active moiety of a small-molecule prodrug Molnupiravir) or MU-UNMC-2 (a SARS-CoV-2 entry inhibitor) at a fixed doses matrix, a synergistic effect was observed, leading to the significant reduction in the dose of the individual compounds to achieve similar inhibition of SARS-CoV-2 replication. Herein, we report that the combination of SRX3177/MPV or SRX3177/UM-UNMC-2 has the potential for further development as a combinational therapy against SARS-CoV-2 and in any future outbreak of beta coronavirus.

Keywords: Combinatorial; Entry inhibitor; MU-UNMC-2; Omicron; RdRp inhibitor; SARS-CoV-2; SRX3177; Triple inhibitor.

Abstract

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