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Exploring the SAR of the β-ketoacyl-ACP synthase inhibitor GSK3011724a and optimization around a genotoxic metabolite

DOI: 10.1021/acsinfecdis.9b00493 DOI Help

Authors: Fraser Cunningham (GlaxoSmithKline) , Jorge Esquivias (GlaxoSmithKline) , Raquel Fernández-menéndez (GlaxoSmithKline) , Arancha Pérez (GlaxoSmithKline) , Ana Guardia (GlaxoSmithKline) , Jaime Escribano (GlaxoSmithKline) , Cristina Rivero (GlaxoSmithKline) , Mythily Vimal (GlaxoSmithKline) , Mónica Cacho (GlaxoSmithKline) , Paco De Dios-antón (GlaxoSmithKline) , María Santos Martínez-martínez (GlaxoSmithKline) , Elena Jiménez (GlaxoSmithKline) , Leticia Huertas Valentín (GlaxoSmithKline) , María José Rebollo-lópez (GlaxoSmithKline) , Eva María López-román (GlaxoSmithKline) , Verónica Sousa-morcuende (GlaxoSmithKline) , Joaquín Rullas (GlaxoSmithKline) , Margaret Neu (GlaxoSmithKline) , Chun-wa Chung (GlaxoSmithKline) , Robert H. Bates (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: March 2020
Diamond Proposal Number(s): 5799

Abstract: 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.

Journal Keywords: KasA; Ames; mutagenicity

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography