Novel small molecule inhibitors for prostate‐specific antigen

Koistinen, Hannu; Wohlfahrt, Gerd; Mattsson, Johanna M.; Wu, Ping; Lahdenperä, Juhani; Stenman, Ulf‐Hǎkan

doi:10.1002/pros.20773

Cited by 41 publications

(38 citation statements)

References 39 publications

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“…and then Tan et al. have identified 1‐acyl‐1,2,4‐triazole derivatives as several KLK‐related peptidases inhibitors (Table ) . The best compound of the triazole family (compound 6b ) showed an IC 50 of 0.4 nM against the KLK7.…”

Section: Nonphysiological Inhibitorsmentioning

confidence: 99%

Inhibitors of kallikrein‐related peptidases: An overview

Masurier

Arama

Amri

et al. 2017

Medicinal Research Reviews

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Kallikrein-related peptidases (KLKs) are a family of 15 secreted serine proteases that are involved in various physiological processes. Their activities are subtly regulated by various endogenous inhibitors, ranging from metallic ions to macromolecular entities such as proteins. Furthermore, dysregulation of KLK activity has been linked to several pathologies, including cancer and skin and inflammatory diseases, explaining the numerous efforts to develop KLK-specific pharmacological inhibitors as potential therapeutic agents. In this review, we focus on the huge repertoire of KLKs inhibitors reported to date with a special emphasis on the diversity of their molecular mechanisms of inhibition.

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Section: Nonphysiological Inhibitorsmentioning

confidence: 99%

Inhibitors of kallikrein‐related peptidases: An overview

Masurier

Arama

Amri

et al. 2017

Medicinal Research Reviews

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“…Due to the required mimicking of a natural active site binding molecule, such inhibitory compounds often contain amino acid derived groups, as the β-lactam derived 2-azetidinone with a Tyr side chain that inhibited KLK3 with an IC 50 of 226 nM and was apparently designed obeying the “rule of five” [275]. In particular, for KLK3 heterocyclic compounds in a structure–activity relationship approach reached an IC 50 of 300 nM [276].…”

Section: Pharmaceutical Approachesmentioning

confidence: 99%

Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs)

2010

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Including the true tissue kallikrein KLK1, kallikrein-related peptidases (KLKs) represent a family of fifteen mammalian serine proteases. While the physiological roles of several KLKs have been at least partially elucidated, their activation and regulation remain largely unclear. This obscurity may be related to the fact that a given KLK fulfills many different tasks in diverse fetal and adult tissues, and consequently, the timescale of some of their physiological actions varies significantly. To date, a variety of endogenous inhibitors that target distinct KLKs have been identified. Among them are the attenuating Zn2+ ions, active site-directed proteinaceous inhibitors, such as serpins and the Kazal-type inhibitors, or the huge, unspecific compartment forming α2-macroglobulin. Failure of these inhibitory systems can lead to certain pathophysiological conditions. One of the most prominent examples is the Netherton syndrome, which is caused by dysfunctional domains of the Kazal-type inhibitor LEKTI-1 which fail to appropriately regulate KLKs in the skin. Small synthetic inhibitory compounds and natural polypeptidic exogenous inhibitors have been widely employed to characterize the activity and substrate specificity of KLKs and to further investigate their structures and biophysical properties. Overall, this knowledge leads not only to a better understanding of the physiological tasks of KLKs, but is also a strong fundament for the synthesis of small compound drugs and engineered biomolecules for pharmaceutical approaches. In several types of cancer, KLKs have been found to be overexpressed, which makes them clinically relevant biomarkers for prognosis and monitoring. Thus, down regulation of excessive KLK activity in cancer and in skin diseases by small inhibitor compounds may represent attractive therapeutical approaches.

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“…40 To elucidate the role of PSA in angiogenesis, Koistinen et al screened a library of nearly 50,000 compounds to discover inhibitors of PSA. 41 Out of the compounds screened only three were identified that inhibited PSA at sub µM concentrations. The active compounds were either benzoxazinone or triazole derivatives, which inhibited PSA with IC 50 values of 300–900 nM and had 10–30 fold specificity vs. chymotrypsin.…”

Section: Discussionmentioning

confidence: 99%

Structural Optimization, Biological Evaluation, and Application of Peptidomimetic Prostate Specific Antigen Inhibitors

et al. 2013

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Prostate-Specific Antigen (PSA) is a serine protease produced at high levels by normal and malignant prostate epithelial cells that is used extensively as a biomarker in the clinical management of prostate cancer. To better understand PSA’s role in prostate cancer progression we prepared a library of peptidyl boronic acid based inhibitors. To enhance selectivity for PSA vs. other serine proteases, we modified the P1 site of the inhibitors to incorporate a bromopropylglycine group. This allowed the inhibitors to participate in halogen bond formation with the serine found at the bottom of the specificity pocket. The best of these Ahx-FSQn(boro)Bpg had PSA Ki of 72 nM and chymotrypsin Ki of 580 nM. In vivo studies using PSA-producing xenografts demonstrated that candidate inhibitors had minimal effect on growth but significantly altered serum levels of PSA. Biodistribution of 125I labeled peptides showed low levels of uptake into tumors compared to other normal tissues.

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Novel small molecule inhibitors for prostate‐specific antigen

Abstract: We found several PSA inhibitors that could be useful tools for studying the role of PSA in cancer models and in normal physiology as showed in angiogenesis model.

Cited by 41 publications

References 39 publications

Inhibitors of kallikrein‐related peptidases: An overview

Inhibitors of kallikrein‐related peptidases: An overview

Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs)

Structural Optimization, Biological Evaluation, and Application of Peptidomimetic Prostate Specific Antigen Inhibitors

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