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

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

  • J Med Chem. 2023 Nov 23;66(22):15380-15408. doi: 10.1021/acs.jmedchem.3c01514.
Simon R Green 1,  Caroline Wilson 1,  Thomas C Eadsforth 1,  Avinash S Punekar 1,  Fabio K Tamaki 1,  Gavin Wood 1,  Nicola Caldwell 1,  Barbara Forte 1,  Neil R Norcross 1,  Michael Kiczun 1,  John M Post 1,  Eva Maria Lopez-Román 2,  Curtis A Engelhart 3,  Iva Lukac 1,  Fabio Zuccotto 1,  Ola Epemolu 1,  Helena I M Boshoff 4,  Dirk Schnappinger 3,  Chris Walpole 5,  Ian H Gilbert 1,  Kevin D Read 1,  Paul G Wyatt 1,  Beatriz Baragaña 1
Affiliations

Affiliations

  • 1 Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • 2 Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid Spain.
  • 3 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, United States.
  • 4 Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, United States.
  • 5 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.
PMID: 37948640 DOI: 10.1021/acs.jmedchem.3c01514
Abstract

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.

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