The Discovery of Compounds That Stimulate the Activity of Kallikrein-Related Peptidase3 (KLK3)

Kallikrein-related peptidase3 (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 invivo and invitro. 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. Target specificity: Successful 3D pharmacophore-based virtual screening resulted in the first small, drug-like molecule that stimulates the activity of kallikrein-related peptidase3 (KLK3, PSA). The compound discovered can be applied to the design of novel KLK3-stimulating compounds with the potential to inhibit tumor angiogenesis and progression of prostate cancer.