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Kallikrein 5 inhibitors identified through structure based drug design in search for a treatment for Netherton Syndrome

DOI: 10.1016/j.bmcl.2019.01.020 DOI Help

Authors: Gemma V. White (GlaxoSmithKline R&D) , Emma V. Edgar (GlaxoSmithKline R&D) , Duncan S. Holmes (GlaxoSmithKline R&D) , Xiao Qing Lewell (GlaxoSmithKline R&D) , John Liddle (GlaxoSmithKline R&D) , Oxana Polyakova (GlaxoSmithKline R&D) , Kathrine J. Smith (GlaxoSmithKline R&D) , James H. Thorpe (GlaxoSmithKline R&D) , Ann L. Walker (GlaxoSmithKline R&D) , Yichen Wang (INSERM UMR1163 Laboratory of Genetic Skin Diseases, Imagine Institute; Université Paris Descartes-Sorbonne Paris Cité) , Robert J. Young (GlaxoSmithKline R&D) , Alain Hovnanian (INSERM UMR1163 Laboratory of Genetic Skin Diseases, Imagine Institute; Université Paris Descartes-Sorbonne Paris Cité)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters

State: Published (Approved)
Published: January 2019
Diamond Proposal Number(s): 5799

Abstract: Netherton syndrome (NS) is a rare and debilitating severe autosomal recessive genetic skin disease with high mortality rates particularly in neonates. NS is caused by loss-of-function SPINK5 mutations leading to unregulated kallikrein 5 (KLK5) and kallikrein 7 (KLK7) activity. Furthermore, KLK5 inhibition has been proposed as a potential therapeutic treatment for NS. Identification of potent and selective KLK5 inhibitors would enable further exploration of the disease biology and could ultimately lead to a treatment for NS. This publication describes how fragmentation of known trypsin-like serine protease (TLSP) inhibitors resulted in the identification of a series of phenolic amidine-based KLK5 inhibitors 1. X-ray crystallography was used to find alternatives to the phenol interaction leading to identification of carbonyl analogues such as lactam 13 and benzimidazole 15. These reversible inhibitors, with selectivity over KLK1 (10–100 fold), provided novel starting points for the guided growth towards suitable tool molecules for the exploration of KLK5 biology.

Journal Keywords: FBDD; KLK1; KLK5; LEKTI; Netherton syndrome; SPINK5; TLSP

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ESRF