Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors

DOI: 10.1016/j.bmcl.2019.126675

Authors: Ann L. Walker (GlaxoSmithKline R&D) , Alexis Denis (GlaxoSmithKline R&D) , Ryan P. Bingham (GlaxoSmithKline R&D) , Anne Boulliot (GlaxoSmithKline R&D) , Emma V. Edgar (GlaxoSmithKline R&D) , Alan Ferrie (GlaxoSmithKline R&D) , Duncan S. Holmes (GlaxoSmithKline R&D) , Alain Laroze (GlaxoSmithKline R&D) , John Liddle (GlaxoSmithKline R&D) , Marie-Helene Fouchet (GlaxoSmithKline R&D) , Alexandre Moquette (GlaxoSmithKline R&D) , Pam Nassau (GlaxoSmithKline R&D) , Andrew C. Pearce (GlaxoSmithKline R&D) , Oxana Polyakova (GlaxoSmithKline R&D) , Kathrine J. Smith (GlaxoSmithKline R&D) , Pamela Thomas (GlaxoSmithKline R&D) , James H. Thorpe (GlaxoSmithKline R&D) , Lionel Trottet (GlaxoSmithKline R&D) , Yichen Wang (Imagine Institute; Université Paris Descarte-Sorbonne Paris Cité) , Alain Hovnanian (Imagine Institute; Université Paris Descarte-Sorbonne Paris Cité)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters , VOL 29

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

Abstract: The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.

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

Diamond Keywords: Netherton Syndrome

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 25/09/2019 11:14

Discipline Tags:

Health & Wellbeing Biochemistry Genetics Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)