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. 2019 Oct 15;29(20):126675.
doi: 10.1016/j.bmcl.2019.126675. Epub 2019 Sep 7.

Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors

Ann L Walker  1 , Alexis Denis  1 , Ryan P Bingham  1 , Anne Bouillot  1 , Emma V Edgar  1 , Alan Ferrie  1 , Duncan S Holmes  1 , Alain Laroze  1 , John Liddle  2 , Marie-Helene Fouchet  1 , Alexandre Moquette  1 , Pam Nassau  1 , Andrew C Pearce  1 , Oxana Polyakova  1 , Kathrine J Smith  1 , Pamela Thomas  1 , James H Thorpe  1 , Lionel Trottet  1 , Yichen Wang  3 , Alain Hovnanian  3
Affiliations

Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors

Ann L Walker et al. Bioorg Med Chem Lett. .

Erratum in

Abstract

The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.

Keywords: KLK1; KLK5; KLKB1; LEKTI; Netherton syndrome; SPINK5.

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