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Identification of the FDA-Approved Drug Pyrvinium as a Novel Inhibitor of PD-1/PD-L1 Interaction

preprint
submitted on 16.04.2021, 13:43 and posted on 19.04.2021, 12:41 by Elena Fattakhova, Jeremy Hofer, Juliette DiFlumeri, Madison Cobb, Timothy Dando, Zachary Romisher, Justin Wellington, Michael Oravic, Madison Radnoff, Sachin Patil

Immune checkpoint blockade involving inhibition of the PD-1/PD-L1 interaction has provided unprecedented clinical benefits in treating a variety of tumors. To date, a total of six antibodies that bind to either PD-1 or PD-L1 protein and in turn inhibit the PD-1/PD-L1 interaction have received clinical approvals. Despite being highly effective, these expensive large biotherapeutics possess several inherent pharmacokinetic limitations that can be successfully overcome through the use of low-molecular-weight inhibitors. One such promising approach involves small-molecule induced dimerization and sequestration of PD-L1, leading to effective PD-1/PD-L1 inhibition. Herein, we present discovery of such potential bioactive PD-L1 dimerizers through a structure- and ligand-based screening of a focused library of approved and investigational drugs worldwide. The most promising compound Pyrvinium, an FDA-approved anthelmintic drug, showed IC50 value of ~29.66 µM. It is noteworthy that Pyrvinium, being an approved drug, may prove especially suitable as a good starting point for further medicinal chemistry efforts, leading to design and development of even more potent structural analogs as selective PD-1/PD-L1 inhibitors. Furthermore, the adopted integrated virtual screening protocol may prove useful in screening other larger databases of lead- and drug-like molecules for hit identification in the domain of small-molecule PD-1/PD-L1 inhibitors.

Funding

W. W. Smith Charitable Trust Cancer Research Grant

History

Email Address of Submitting Author

spatil@widener.edu

Institution

Widener University

Country

USA

ORCID For Submitting Author

https://orcid.org/0000-0002-1354-0386

Declaration of Conflict of Interest

The authors declare no conflict of interest.

Version Notes

Manuscript (4/13/2021)

Exports