A Potent and Selective Kallikrein-5 Inhibitor Delivers High Pharmacological Activity in Skin from Patients with Netherton Syndrome

  • J Invest Dermatol. 2021 Sep;141(9):2272-2279. doi: 10.1016/j.jid.2021.01.029.
John Liddle  1 ,  Veronique Beneton  2 ,  Matthew Benson  1 ,  Ryan Bingham  1 ,  Anne Bouillot  2 ,  Anne-Benedicte Boullay  2 ,  Eloisa Brook  1 ,  Jenni Cryan  1 ,  Alexis Denis  2 ,  Emma Edgar  1 ,  Alan Ferrie  1 ,  Marie-Helene Fouchet  2 ,  Didier Grillot  2 ,  Duncan S Holmes  1 ,  Ashleigh Howes  1 ,  Gael Krysa  2 ,  Alain Laroze  2 ,  Mark Lennon  1 ,  Fiona McClure  1 ,  Alexandre Moquette  2 ,  Edwige Nicodeme  2 ,  Brandon Santiago  3 ,  Leandro Santos  3 ,  Kathrine J Smith  1 ,  James H Thorpe  1 ,  Gary Thripp  1 ,  Lionel Trottet  2 ,  Ann L Walker  1 ,  Simon A Ward  1 ,  Yichen Wang  4 ,  Steve Wilson  1 ,  Andrew C Pearce  1 ,  Alain Hovnanian  5
Affiliations
  • 1. Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom.
  • 2. GlaxoSmithKline, Paris, France.
  • 3. Discovery and Preclinical Development, GSK Dermatology Unit, Collegeville, Pennsylvania, USA.
  • 4. Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France.
  • 5. Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France; University of Paris, Paris, France; Department of Genetics, Necker hospital for sick children, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: [email protected].
PMID: 33744298 DOI: 10.1016/j.jid.2021.01.029
Abstract

Regulation of proteolytic activity in the skin plays a pivotal role in epidermal homeostasis. This is best exemplified in Netherton syndrome, a severe genetic skin condition caused by loss-of-function mutations in the gene Serine Protease Inhibitor Kazal-type 5 encoding lympho-epithelial Kazal-type-related inhibitor, a Serine Protease Inhibitor that regulates Kallikrein (KLK)-related peptidase 5, 7, and 14 activities. KLK5 plays a central role in stratum corneum shedding and inflammatory cell signaling, activates KLK7 and KLK14, and is therefore an optimal therapeutic target. We aimed to identify a potent and selective small-molecule inhibitor of KLK5 amenable to epidermal delivery. GSK951 was identified using a structure-based design strategy and showed a half maximal inhibitory concentration of 250 pM for KLK5 and greater than 100-fold selectivity over KLK7 and KLK14. Cocrystal structure analysis identified the critical catalytic site interactions to a surrogate for KLK5. Topical application of GSK951-containing cream inhibited KLK5 activity in TgKLK5 mouse skin, reduced transepidermal water loss, and decreased proinflammatory cytokine expression. GSK951 achieved high concentrations in healthy human epidermis following topical application in a cream formulation. Finally, KLK5 protease activity was increased in stratum corneum of patients with Netherton syndrome and significantly inhibited by GSK951. These findings unveil a KLK5-specific small-molecule inhibitor with a high therapeutic potential for patients with Netherton syndrome.

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