A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA

Daigo Inoyama; Divya Awasthi; Glenn C Capodagli; Kholiswa Tsotetsi; Paridhi Sukheja; Matthew Zimmerman; Shao-Gang Li; Ravindra Jadhav; Riccardo Russo; Xin Wang; Courtney Grady; Todd Richmann; Riju Shrestha; Liping Li; Yong-Mo Ahn; Hsin Pin Ho Liang; Marizel Mina; Steven Park; David S Perlin; Nancy Connell; Véronique Dartois; David Alland; Matthew B Neiditch; Pradeep Kumar; Joel S Freundlich

doi:10.1016/j.chembiol.2020.02.007

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A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA

Journal article

Peer reviewed

A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA

Daigo Inoyama, Divya Awasthi, Glenn C Capodagli, Kholiswa Tsotetsi, Paridhi Sukheja, Matthew Zimmerman, Shao-Gang Li, Ravindra Jadhav, Riccardo Russo, Xin Wang, …

Cell chemical biology, Vol.27(5), pp.560-570.e10

05/21/2020

DOI: https://doi.org/10.1016/j.chembiol.2020.02.007

PMID: 32197094

Abstract

pharmacokinetics

Mycobacterium tuberculosis

antitubercular

JSF-3285

structure-based design

KasA

Published Mycobacterium tuberculosis β-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Biochemical, genetic, and X-ray studies confirmed JSF-3285 targets KasA. JSF-3285 offers substantial activity in an acute mouse model of infection and in the corresponding chronic infection model, with efficacious reductions in colony-forming units at doses as low as 5 mg/kg once daily orally and improvement of the efficacy of front-line drugs isoniazid or rifampicin. JSF-3285 is a promising preclinical candidate for tuberculosis. [Display omitted] •A structure-based optimization of the KasA inhibitor DG167 led to JSF-3285•The inhibitor evolution focused on metabolic stability and mouse plasma PK•JSF-3285 is efficacious in a mouse model of chronic TB infection at 5 mg/kg•JSF-3285 represents a preclinical lead compound for TB Inoyama et al. disclose the optimization of an indazole antitubercular targeting the β-ketoacyl-ACP synthase KasA. A structure-based approach has overcome significant issues with mouse metabolic stability and pharmacokinetics. A preclinical drug candidate has been delivered with efficacy in a mouse model of chronic M. tuberculosis infection at 5 mg/kg dosing.

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Title: A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA
Creators: Daigo Inoyama - Department of Pharmacology, Physiology, and Neuroscience, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Divya Awasthi - Department of Pharmacology, Physiology, and Neuroscience, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Glenn C Capodagli - Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, USA
Kholiswa Tsotetsi - Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Paridhi Sukheja - Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Matthew Zimmerman - Public Health Research Institute, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Shao-Gang Li - Department of Pharmacology, Physiology, and Neuroscience, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Ravindra Jadhav - Department of Pharmacology, Physiology, and Neuroscience, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Riccardo Russo - Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Xin Wang - Department of Pharmacology, Physiology, and Neuroscience, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Courtney Grady - Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Todd Richmann - Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Riju Shrestha - Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Liping Li - Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Yong-Mo Ahn - Department of Pharmacology, Physiology, and Neuroscience, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Hsin Pin Ho Liang - Public Health Research Institute, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Marizel Mina - Public Health Research Institute, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Steven Park - Public Health Research Institute, Rutgers University – New Jersey Medical School, Newark, NJ, USA
David S Perlin - Public Health Research Institute, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Nancy Connell - Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Véronique Dartois - Public Health Research Institute, Rutgers University – New Jersey Medical School, Newark, NJ, USA
David Alland - Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Matthew B Neiditch - Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, USA
Pradeep Kumar - Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Joel S Freundlich - Department of Pharmacology, Physiology, and Neuroscience, Rutgers University – New Jersey Medical School, Newark, NJ, USA
Publication Details: Cell chemical biology, Vol.27(5), pp.560-570.e10
Date published: 05/21/2020
Publisher: Elsevier Ltd
Academic Unit: Medicinal Chemistry (EMSOP); Public Health Research Institute; Microbiology, Biochemistry and Molecular Genetics (NJMS); Pharmacology (NJMS); Medicine - Infectious Diseases (NJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031654823904646