PDBsum entry 5nrf

Hydrolase

PDB id: 5nrf

Contents

Protein chain

377 a.a.

Ligands

95Q

GOL

Waters ×200

References listed in PDB file

Key reference

• Title: Targeting acidic mammalian chitinase is effective in animal model of asthma.
• Authors: M.Mazur, J.Olczak, S.Olejniczak, R.Koralewski, W.Czestkowski, A.Jedrzejczak, J.Golab, K.Dzwonek, B.Dymek, P.L.Sklepkiewicz, A.Zagozdzon, T.Noonan, K.Mahboubi, B.Conway, R.Sheeler, P.Beckett, W.M.Hungerford, A.Podjarny, A.Mitschler, A.Cousido-Siah, F.Fadel, A.Golebiowski.
• Ref.: J Med Chem, 2018, 61, 695-710. [DOI no: 10.1021/acs.jmedchem.7b01051]
• PubMed id: 29283260
• DOI number: 10.1021/ACS.JMEDCHEM.7B01051

Abstract

This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC₅₀values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150× against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound 7f in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma.

Secondary reference #1

• Title: Targeting acidic mammalian chitinase is effective in model of asthma
• Authors: M.Mazur, J.Olczak, S.Olejniczak, R.Koralewski, W.Czestkowa.Jedrzejczak, J.Golab, K.Dzwonek, B.Dymek, P.Sklepkiewica.Zagozdzon, T.Noonan, K.Mahboubi, B.Conway, R.Sheeler, P.Beckett, W.M.Hungerford, A.Podjarny, A.Mitschler, A.Cousido-Siah, F.Fadel, A.Golebiowski.
• Ref.: TO BE PUBLISHED ...