Discovery and validation of 2-styryl substituted benzoxazin-4-ones as a novel scaffold for rhomboid protease inhibitors

0490090 - ÚOCHB 2019 RIV GB eng J - Journal Article
Goel, P. - Jumpertz, T. - Tichá, Anežka - Ogorek, I. - Mikles, David C. - Hubálek, Martin - Pietrzik, C. U. - Stříšovský, Kvido - Schmidt, B. - Weggen, S.
Discovery and validation of 2-styryl substituted benzoxazin-4-ones as a novel scaffold for rhomboid protease inhibitors.
Bioorganic and Medicinal Chemistry Letters. Roč. 28, č. 8 (2018), s. 1417-1422. ISSN 0960-894X. E-ISSN 1464-3405
R&D Projects: GA MŠMT(CZ) LK11206; GA MŠMT LO1302
EU Projects: European Commission(XE) 304154 - Rhomboid substrates
Institutional support: RVO:61388963
Keywords : rhomboid proteases * intramembrane proteases * benzoxazinones * molecular docking * inhibition
OECD category: Biochemistry and molecular biology
Impact factor: 2.448, year: 2018

Rhomboids are intramembrane serine proteases with diverse physiological functions in organisms ranging from archaea to humans. Crystal structure analysis has provided a detailed understanding of the catalytic mechanism, and rhomboids have been implicated in various disease contexts. Unfortunately, the design of specific rhomboid inhibitors has lagged behind, and previously described small molecule inhibitors displayed insufficient potency and/or selectivity. Using a computer-aided approach, we focused on the discovery of novel scaffolds with reduced liabilities and the possibility for broad structural variations. Docking studies with the E. coli rhomboid GlpG indicated that 2-styryl substituted benzoxazinones might comprise novel rhomboid inhibitors. Protease in vitro assays confirmed activity of 2-styryl substituted benzoxazinones against GlpG but not against the soluble serine protease alpha-chymotrypsin. Furthermore, mass spectrometry analysis demonstrated covalent modification of the catalytic residue Ser201, corroborating the predicted mechanism of inhibition and the formation of an acyl enzyme intermediate. In conclusion, 2-styryl substituted benzoxazinones are a novel rhomboid inhibitor scaffold with ample opportunity for optimization.
Permanent Link: http://hdl.handle.net/11104/0284386