Targeting the kallikrein-related peptidases for drug development.

Kallikrein-related peptidases (KLKs) constitute a family of 15 serine proteases. Recent studies have shed light on key physiological functions of KLK enzymes and implicate their deregulation in major human pathologies such as neurodegenerative and inflammatory diseases, skin conditions, asthma, and cancer. Consequently, KLKs have emerged as novel targets for pharmacological intervention. Given the pleiotropic roles of KLKs, both activators and inhibitors of KLK activities are of therapeutic interest. For example, inhibitors of hyperactive KLKs in the epidermis would be effective against excess skin desquamation and inflammation, whereas KLK activators could benefit hyperkeratosis caused by diminished KLK proteolysis. Expression of active KLKs by cancer cells and tissues can be exploited to target prodrugs that are proteolytically cleaved to release a cytotoxic compound or a cytolytic toxin at the site of KLK protease activity. Here, we review current approaches for the design and testing of KLK-based therapeutics.