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research article

Leads for antitubercular compounds from kinase inhibitor library screens

Magnet, Sophie  
•
Hartkoorn, Ruben C.  
•
Székely, Rita
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2010
Tuberculosis

Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find antimycobacterial scaffolds, we screened a kinase inhibitor library of more than 12,000 compounds using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and a target-based assay with the protein kinase PknA. Seventeen "hits" came from the whole cell-based screening approach, from which three displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10μM and were non-mutagenic and non-cytotoxic. Two of these hits were specific for M. tuberculosis versus C. glutamicum and none of them was found to inhibit the essential serine/threonine protein kinases, PknA and PknB present in both bacteria. One of the most active hits, VI-18469, had a benzoquinoxaline pharmacophore while another, VI-9376, is structurally related to a new class of antimycobacterial agents, the benzothiazinones (BTZ). Like the BTZ, VI-9376 was shown to act on the essential enzyme decaprenylphosphoryl-β-D-ribose 2'-epimerase, DprE1, required for arabinan synthesis.

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Type
research article
DOI
10.1016/j.tube.2010.09.001
Web of Science ID

WOS:000283739000005

Author(s)
Magnet, Sophie  
Hartkoorn, Ruben C.  
Székely, Rita
Pató, János
Triccas, James A.
Schneider, Patricia
Szántai-Kis, Csaba
Orfi, László
Chambon, Marc  
Banfi, Damiano  
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Date Issued

2010

Published in
Tuberculosis
Volume

90

Issue

6

Start page

354

End page

60

Subjects

Tuberculosis

•

Screening

•

Kinase inhibitor

•

Quinoxaline

•

Serine/threonine protein Kinase (STPK)

•

DprE1

•

Mycobacterium-Tuberculosis

•

Pathogenic Mycobacteria

•

Protein-Kinases

•

Drug Discovery

•

Pknb

•

Identification

•

Macrophages

•

Clofazimine

•

Candidate

•

Resistant

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
PTCB  
UPCOL  
Available on Infoscience
November 8, 2010
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/57258
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