Structure guided drug design to develop kallikrein 5 inhibitors to treat Netherton syndrome

Ann L Walker; Ryan P Bingham; Emma V Edgar; Alan Ferrie; Duncan S Holmes; John Liddle; Oxana Polyakova; Monika Rella; Kathrine J Smith; James H Thorpe; Yichen Wang; Gemma V White; Robert J Young; Alain Hovnanian

doi:10.1016/j.bmcl.2019.04.022

Structure guided drug design to develop kallikrein 5 inhibitors to treat Netherton syndrome

Bioorg Med Chem Lett. 2019 Jun 15;29(12):1454-1458. doi: 10.1016/j.bmcl.2019.04.022. Epub 2019 Apr 12.

Affiliations

¹ GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: Ann.L.Walker@gsk.com.
² GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
³ INSERM UMR1163 Laboratory of Genetic Skin Diseases, Imagine Institute and Université Paris Descarte - Sorbonne Paris Cité, Paris, France.

PMID: 31005442
DOI: 10.1016/j.bmcl.2019.04.022

Abstract

The connection between Netherton syndrome and overactivation of epidermal/dermal proteases particularly KLK5 has been well established. To treat sufferers of this severe condition we wished to develop a topical KLK5 inhibitor in order to normalise epidermal shedding and reduce the associated inflammation and itching. In this paper we describe structure-based optimisation of a series of brightly coloured weak KLK5 inhibitors into colourless, non-irritant molecules with good KLK5 activity and selectivity over a range of serine proteases.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Design*
Humans
Kallikreins / antagonists & inhibitors*
Netherton Syndrome / drug therapy*

Substances

Kallikreins