Urokinase plasminogen activator as an anti-metastasis target: inhibitor design principles, recent amiloride derivatives, and issues with human/mouse species selectivity

Nehad S El Salamouni; Benjamin J Buckley; Marie Ranson; Michael J Kelso; Haibo Yu

doi:10.1007/s12551-021-00921-7

Urokinase plasminogen activator as an anti-metastasis target: inhibitor design principles, recent amiloride derivatives, and issues with human/mouse species selectivity

Biophys Rev. 2022 Jan 6;14(1):277-301. doi: 10.1007/s12551-021-00921-7. eCollection 2022 Feb.

Authors

Nehad S El Salamouni^{1

2

3}, Benjamin J Buckley^{1

2

3}, Marie Ranson^{1

2

3}, Michael J Kelso^{1

2

3}, Haibo Yu^{1

2

3}

Affiliations

¹ School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522 Australia.
² Molecular Horizons, University of Wollongong, Wollongong, NSW 2522 Australia.
³ Illawarra Health and Medical Research Institute, Wollongong, NSW 2522 Australia.

Abstract

The urokinase plasminogen activator (uPA) is a widely studied anticancer drug target with multiple classes of inhibitors reported to date. Many of these inhibitors contain amidine or guanidine groups, while others lacking these groups show improved oral bioavailability. Most of the X-ray co-crystal structures of small molecule uPA inhibitors show a key salt bridge with the side chain carboxylate of Asp189 in the S1 pocket of uPA. This review summarises the different classes of uPA inhibitors, their binding interactions and experimentally measured inhibitory potencies and highlights species selectivity issues with attention to recently described 6-substituted amiloride and 5‑N,N-(hexamethylene)amiloride (HMA) derivatives.

Keywords: Species selectivity; Urokinase plasminogen activator; X-ray structures; uPA inhibitors.

Publication types

Review