PDBsum entry 6ic7

Hydrolase

PDB id: 6ic7

Contents

Protein chains

118 a.a.

162 a.a.

68 a.a.

Ligands

NAG-NAG-BMA-MAN-MAN

NAG ×2

H9H

Metals

_CL

Waters ×349

References listed in PDB file

Key reference

• Title: Structure-Based design and in vivo anti-Arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin c.
• Authors: B.Korkmaz, A.Lesner, M.Wysocka, A.Gieldon, M.Håkansson, F.Gauthier, D.T.Logan, D.E.Jenne, C.Lauritzen, J.Pedersen.
• Ref.: Biochem Pharmacol, 2019, 164, 349-367. [DOI no: 10.1016/j.bcp.2019.04.006]
• PubMed id: 30978322

Abstract

Cathepsin C (CatC) is a dipeptidyl-exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4) by removing their N-terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a therapeutic strategy to suppress excessive protease activities in various neutrophil mediated diseases. We designed and synthesized a series of dipeptidyl cyclopropyl nitrile compounds as putative CatC inhibitors. One compound, IcatC_XPZ-01 ((S)-2-amino-N-((1R,2R)-1-cyano-2-(4'-(4-methylpiperazin-1-ylsulfonyl)biphenyl-4-yl)cyclopropyl)butanamide)) was identified as a potent inhibitor of both human and rodent CatC. In mice, pharmacokinetic studies revealed that IcatC_XPZ-01 accumulated in the bone marrow reaching levels suitable for CatC inhibition. Subcutaneous administration of IcatC_XPZ-01 in a monoclonal anti-collagen antibody induced mouse model of rheumatoid arthritis resulted in statistically significant anti-arthritic activity with persistent decrease in arthritis scores and paw thickness.