Structure-Based design, synthesis and sAR of a novel series of thiopheneamidine urokinase plasminogen activator inhibitors

Subasinghe, Nalin L.; Illig, Carl R.; Hoffman, James B.; Rudolph, Matthias; Wilson, Kenneth J.; Söll, Richard; Randle, Troy; Lewandowski, Frank; Zhang, Marie; Bone, Roger; Spurlino, John; DesJarlais, Renée L.; Deckman, Ingrid C.; Molloy, Christopher J.; Manthey, Carl L.; Zhou, Zhau; Sharp, Celia; Maguire, Diane; Crysler, Carl; Grasberger, Bruce

doi:10.1016/s0960-894x(01)00247-5

Cited by 14 publications

(3 citation statements)

References 14 publications

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“…Like many other serine proteases, experimental validation of this mechanism has been provided via mutation of Ser195 to Ala (S195A) (Alipranti et al 2020;Gong et al 2016) or Met (S195M) (Masih et al 2020) to produce catalytically inactive variants. As with other TLSPs, most early uPA inhibitors were arginine-mimetics, comprising an aromatic moiety substituted with an amidine (Klinghofer et al 2001;Künzel et al 2002;Mackman et al 2002;Rudolph et al 2002;Stürzebecher et al 1999;Subasinghe et al 2001) or guanidine (Barber et al 2004;Fish et al 2007;Karthikeyan et al 2009;Sperl et al 2000) group. These analogues were highly basic (pKa > 11), positively charged at the physiological pH, showed poor pharmacokinetic properties and suffered low oral bioavailability (Rockway et al 2002).…”

Section: Catalytic Mechanism Of Upamentioning

confidence: 99%

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

et al. 2022

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Section: Catalytic Mechanism Of Upamentioning

confidence: 99%

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

et al. 2022

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“…uPA residues are shown in cyan. As with other TLSPs, most early uPA inhibitors were arginine-mimetics, comprising an aromatic moiety substituted with an amidine (Klinghofer et al 2001;Künzel et al 2002;Mackman et al 2002;Rudolph et al 2002;Stürzebecher et al 1999;Subasinghe et al 2001) or guanidine (Barber et al 2004;Fish et al 2007;Karthikeyan et al 2009;Sperl et al 2000) group. These analogues were highly basic (pKa > 11), positively charged at the physiological pH, showed poor pharmacokinetic properties and suffered low oral bioavailability (Rockway et al 2002).…”

Section: Catalytic Mechanism Of Upamentioning

confidence: 99%

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

Salamouni¹,

Buckley²,

Ranson³

et al. 2021

Preprint

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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 show improved oral bioavailability. Most of the X-ray co-crystal structures of small molecule uPA inhibitors show a key salt bridge between 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 recent 6-substituted amiloride and 5‐N,N-(hexamethylene)amiloride (HMA) derivatives.

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“…85,86 Urokinase-Type Plasminogen Activator uPA is a serine protease with a well-defined active site and therefore a very attractive target for inhibitors. [87][88][89] Several academic and industry research groups pursued small-molecule inhibitors of uPA for many years, but only one set of compounds actually entered the clinic. Many of these inhibitors were initially peptidic or peptidomimetic-based molecules.…”

Section: Drug Targetsmentioning

confidence: 99%

The Apparent uPA/PAI-1 Paradox in Cancer: More than Meets the Eye

Kwaan

Mazar²,

McMahon³

2013

Semin Thromb Hemost

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The expression of several components of the plasminogen-plasmin (P-P) system in tumor tissues has been shown to have prognostic significance in many human cancers, including those of the breast, prostate, lung, brain, ovary, stomach, colon, rectum, oral cavity, kidney, and bone. Mechanisms of action of the individual components have been extensively studied in tumor cells in vitro and in animal models. By interrupting various putative pathways involved in tumor progression in several experimental tumor models in animals, varying degrees of tumor control have been achieved. However, these efforts have thus far not been able to exert any impact in oncologic clinical practice. A possible explanation is our incomplete understanding of the complex involvement of the P-P system and its interactions with other tumorigenic factors. In this article, the role of various members of the P-P system in cancer is reviewed. Proteolysis via the urokinase-type plasminogen activator-plasminogen activation pathway tends to enhance tumor growth and invasion, and its natural inhibitor plasminogen activator inhibitor type 1 may also enhance tumor growth through the inhibition of apoptosis, enhancing cell proliferation and the promotion of angiogenesis. Meaningful drug designs for therapeutic intervention require a thorough understanding of the role of all of the components involved in this complex mechanism of tumor progression.

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Structure-Based design, synthesis and sAR of a novel series of thiopheneamidine urokinase plasminogen activator inhibitors

Cited by 14 publications

References 14 publications

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

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

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

The Apparent uPA/PAI-1 Paradox in Cancer: More than Meets the Eye

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