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Exploring the SAR of the β-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite

2020; American Chemical Society; Volume: 6; Issue: 5 Linguagem: Inglês

10.1021/acsinfecdis.9b00493

2373-8227

Fraser Cunningham, Jorge Esquivias, Raquel Fernández Menéndez, Arancha Pérez, A.C. Guardia, Jaime Escribano, Cristina Rivero, Mythily Vimal, Mónica Cacho, Paco de Dios-Antón, María Santos Martínez, Elena Jiménez, Leticia Huertas Valentín, María José Rebollo-López, Eva María López-Román, Verónica Sousa-Morcuende, Joaquín Rullás, Margaret Neu, Chun‐wa Chung, Robert H. Bates,

Cancer therapeutics and mechanisms

In the course of optimizing a novel indazole sulfonamide series that inhibits β-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.