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.
Ann L Walker  1 ,  Ryan P Bingham  2 ,  Emma V Edgar  2 ,  Alan Ferrie  2 ,  Duncan S Holmes  2 ,  John Liddle  2 ,  Oxana Polyakova  2 ,  Monika Rella  2 ,  Kathrine J Smith  2 ,  James H Thorpe  2 ,  Yichen Wang  3 ,  Gemma V White  2 ,  Robert J Young  2 ,  Alain Hovnanian  3
Affiliations
  • 1. GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: [email protected].
  • 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.
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