Discovery and structure-activity relationship study of 1,3,6-trisubstituted 1,4-diazepane-7-ones as novel human kallikrein 7 inhibitors
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Authors: Murafuji, Hidenobu; Sakai, Hiroki; Goto, Megumi; Imajo, Seiichi; Sugawara, Hajime; Muto, Tsuyoshi
Abstract
Compound 1, composed of a 1,3,6-trisubstituted 1,4-diazepane-7-one, was discovered as a novel human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme, SCCE) inhibitor, and its derivatives were synthesized and evaluated. Structure-activity relationship studies of the amidoxime unit and benzoic acid part of this new scaffold led to the identification of 25 and 34, which were more potent than the hit compound, 1. The X-ray co-crystal structure of compound 25 and human KLK7 revealed the characteristic interactions and enabled explanations of the structure-activity relationship. (C) 2017 Elsevier Ltd. All rights reserved.
Kallikrein-related peptidase 14 is the second KLK protease targeted by the serpin vaspin
BIOLOGICAL CHEMISTRY
Authors: Ulbricht, David; Tindall, Catherine A.; Oertwig, Kathrin; Hanke, Stefanie; Straeter, Norbert; Heiker, John T.
Abstract
Kallikrein-related peptidases KLK5, KLK7 and KLK14 are important proteases in skin desquamation and aberrant KLK activity is associated with inflammatory skin diseases such as Netherton syndrome but also with various serious forms of cancer. Previously, we have identified KLK7 as the first protease target of vaspin (Serpin A12). Here, we report KLK14 as a second KLK protease to be inhibited by vaspin. In conclusion, vaspin represents a multi-specific serpin targeting the kallikrein proteases KLK7 and KLK14, with distinct exosites regulating recognition of these target proteases and opposing effects of heparin binding on the inhibition reaction.
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