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Exploring the SAR of the β‑Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite
journal contribution
posted on 2020-03-20, 15:33 authored by Fraser Cunningham, Jorge Esquivias, Raquel Fernández-Menéndez, Arancha Pérez, Ana Guardia, Jaime Escribano, Cristina Rivero, Mythily Vimal, Mónica Cacho, Paco de Dios-Antón, María Santos Martínez-Martínez, Elena Jiménez, Leticia Huertas Valentín, María José Rebollo-López, Eva María López-Román, Verónica Sousa-Morcuende, Joaquín Rullas, Margaret Neu, Chun-wa Chung, Robert H. BatesIn 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.
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Mycobacterium tuberculosisoptimization effortsKetoacyl-ACPbinding siteGSKKasAExploringstericInhibitorunderexplored targetaniline moietymutagenic aniline metaboliteTBβ- ketoacyl-ACP synthaseSynthaseliabilityOptimizationSAR spacenovel indazole sulfonamide series3011724AGenotoxic Metabolitefuture discovery efforts
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