2. Academic Validation
  3. A Potent and Selective Kallikrein-5 Inhibitor Delivers High Pharmacological Activity in Skin from Patients with Netherton Syndrome

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

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: alain.hovnanian@inserm.fr.
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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