Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity.

Autor: Green SR; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Wilson C; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Eadsforth TC; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Punekar AS; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Tamaki FK; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Wood G; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Caldwell N; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Forte B; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Norcross NR; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Kiczun M; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Post JM; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Lopez-Román EM; Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid Spain., Engelhart CA; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, United States., Lukac I; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Zuccotto F; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Epemolu O; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Boshoff HIM; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, United States., Schnappinger D; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, United States., Walpole C; Structural Genomics Consortium, Research Institute of the McGill University Health Centre, 1001 Boulevard Décarie, Site Glen Block E, ES1.1614, Montréal, QC H4A 3J1, Canada., Gilbert IH; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Read KD; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Wyatt PG; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Baragaña B; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2023 Nov 23; Vol. 66 (22), pp. 15380-15408. Date of Electronic Publication: 2023 Nov 10.
DOI: 10.1021/acs.jmedchem.3c01514
Abstrakt: There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality of TB and to combat resistance to current treatments. Through both chemical and genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential for mycobacterial survival and as an attractive target for Mycobacterium tuberculosis growth inhibitors. A benzofuran series of inhibitors that targeted the Pks13 thioesterase domain, failed to progress to preclinical development due to concerns over cardiotoxicity. Herein, we report the identification of a novel oxadiazole series of Pks13 inhibitors, derived from a high-throughput screening hit and structure-guided optimization. This new series binds in the Pks13 thioesterase domain, with a distinct binding mode compared to the benzofuran series. Through iterative rounds of design, assisted by structural information, lead compounds were identified with improved antitubercular potencies (MIC < 1 μM) and in vitro ADMET profiles.
Databáze: MEDLINE