title: The discovery of compounds that stimulate the activity of kallikrein-related peptidase 3 (KLK3).
abstract: Kallikrein-related peptidase 3 (KLK3), also known as prostate-specific antigen (PSA), is the most useful biomarker for prostate cancer (PCa). KLK3 is suggested to play a role in regulating cancer growth through anti-angiogenic activity in vivo and in vitro. This feature, together with its specificity for prostate tissue, makes KLK3 an intriguing target for the design of new therapies for PCa. 3D pharmacophores for KLK3-stimulating compounds were generated based on peptides that bind specifically to KLK3 and increase its enzymatic activity. As a result of pharmacophore-based virtual screening, four small, drug-like compounds with affinity for KLK3 were discovered and validated by capillary differential scanning calorimetry. One of the compounds also stimulated the activity of KLK3, and is therefore the first published small molecule with such an activity.
authors.affiliation: School of Pharmacy, Pharmaceutical Chemistry, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Henna.Harkonen@uef.fi
authors.forename: Henna H
authors.initials: HH
authors.lastname: Härkönen
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Mattsson
authors.forename: Juha A E
authors.initials: JA
authors.lastname: Määttä
authors.forename: Ulf-Håkan
authors.initials: UH
authors.lastname: Stenman
authors.forename: Hannu
authors.initials: H
authors.lastname: Koistinen
authors.forename: Sanni
authors.initials: S
authors.lastname: Matero
authors.forename: Björn
authors.initials: B
authors.lastname: Windshügel
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.forename: Maija
authors.initials: M
authors.lastname: Lahtela-Kakkonen
mesh_terms: D001665:Binding Sites; D002152:Calorimetry, Differential Scanning; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007610:Kallikreins / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D017430:Prostate-Specific Antigen; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D011480:Protease Inhibitors; D054852:Small Molecule Libraries; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen