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Proc Natl Acad Sci U S A. 2016 Dec 6;113(49):E7880-E7889. Epub 2016 Nov 18.

Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology.

Author information

1
Therapeutic Discovery Sciences, X-Chem Pharmaceuticals, Waltham, MA 02453; hsoutter@x-chemrx.com Jon.Read@astrazeneca.com.
2
Discovery Chemistry, X-Chem Pharmaceuticals, Waltham, MA 02453.
3
X-Chem Pharmaceuticals, Waltham, MA 02453.
4
Therapeutic Discovery Sciences, X-Chem Pharmaceuticals, Waltham, MA 02453.
5
Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
6
Scientific Computing, X-Chem Pharmaceuticals, Waltham, MA 02453.
7
Lead Discovery, X-Chem Pharmaceuticals, Waltham, MA 02453.
8
Morphic Therapeutic, Waltham, MA 02451.
9
Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Waltham, MA 02451.
10
Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Macclesfield SK10 4TG, United Kingdom.
11
Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge CB4 0WG, United Kingdom.
12
AstraZeneca India Private Ltd., Hebbal, Bangalore 560 024, India.
13
Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge CB4 0WG, United Kingdom; hsoutter@x-chemrx.com Jon.Read@astrazeneca.com.

Abstract

Millions of individuals are infected with and die from tuberculosis (TB) each year, and multidrug-resistant (MDR) strains of TB are increasingly prevalent. As such, there is an urgent need to identify novel drugs to treat TB infections. Current frontline therapies include the drug isoniazid, which inhibits the essential NADH-dependent enoyl-acyl-carrier protein (ACP) reductase, InhA. To inhibit InhA, isoniazid must be activated by the catalase-peroxidase KatG. Isoniazid resistance is linked primarily to mutations in the katG gene. Discovery of InhA inhibitors that do not require KatG activation is crucial to combat MDR TB. Multiple discovery efforts have been made against InhA in recent years. Until recently, despite achieving high potency against the enzyme, these efforts have been thwarted by lack of cellular activity. We describe here the use of DNA-encoded X-Chem (DEX) screening, combined with selection of appropriate physical properties, to identify multiple classes of InhA inhibitors with cell-based activity. The utilization of DEX screening allowed the interrogation of very large compound libraries (1011 unique small molecules) against multiple forms of the InhA enzyme in a multiplexed format. Comparison of the enriched library members across various screening conditions allowed the identification of cofactor-specific inhibitors of InhA that do not require activation by KatG, many of which had bactericidal activity in cell-based assays.

KEYWORDS:

DNA-encoded X-Chem technology; DNA-encoded libraries; InhA; Mycobacterium tuberculosis; multidrug resistance

PMID:
27864515
PMCID:
PMC5150407
DOI:
10.1073/pnas.1610978113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

H.H.S., P.C., M.A.C., J.W.C., M.-A.G., S.H., A.D.K., K.M.K., E.A.S., and Y.Z. are employees of X-Chem Pharmaceuticals. DNA-encoded X-Chem technology (DEX) is a proprietary drug discovery platform discovered and developed by employees of X-Chem. A.D.F., G.D., E.R.S., J.B., P.M., and J.A.R. are employees of AstraZeneca.

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