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Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor.

ABSTRACT: Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.

SUBMITTER: Martinez-Hoyos M

PROVIDER: S-EPMC4919555 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor.

Martínez-Hoyos María M Perez-Herran Esther E Gulten Gulcin G Encinas Lourdes L Álvarez-Gómez Daniel D Alvarez Emilio E Ferrer-Bazaga Santiago S García-Pérez Adolfo A Ortega Fátima F Angulo-Barturen Iñigo I Rullas-Trincado Joaquin J Blanco Ruano Delia D Torres Pedro P Castañeda Pablo P Huss Sophie S Fernández Menéndez Raquel R González Del Valle Silvia S Ballell Lluis L Barros David D Modha Sundip S Dhar Neeraj N Signorino-Gelo François F McKinney John D JD García-Bustos Jose Francisco JF Lavandera Jose Luis JL Sacchettini James C JC Jimenez M Soledad MS Martín-Casabona Nuria N Castro-Pichel Julia J Mendoza-Losana Alfonso A

EBioMedicine 20160508

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhib ...[more]

PMID: 27428438

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Project description:BackgroundAn important mechanism, by which cancer cells achieve immune escape, is the release of extracellular adenosine into their microenvironment. Adenosine activates adenosine A2A and A2B receptors on immune cells constituting one of the strongest immunosuppressive mediators. In addition, extracellular adenosine promotes angiogenesis, tumor cell proliferation, and metastasis. Cancer cells upregulate ectonucleotidases, most importantly CD39 and CD73, which catalyze the hydrolysis of extracellular ATP to AMP (CD39) and further to adenosine (CD73). Inhibition of CD39 is thus expected to be an effective strategy for the (immuno)therapy of cancer. However, suitable small molecule inhibitors for CD39 are not available. Our aim was to identify drug-like CD39 inhibitors and evaluate them in vitro.MethodsWe pursued a repurposing approach by screening a self-compiled collection of approved, mostly ATP-competitive protein kinase inhibitors, on human CD39. The best hit compound was further characterized and evaluated in various orthogonal assays and enzyme preparations, and on human immune and cancer cells.ResultsThe tyrosine kinase inhibitor ceritinib, a potent anticancer drug used for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer, was found to strongly inhibit CD39 showing selectivity versus other ectonucleotidases. The drug displays a non-competitive, allosteric mechanism of CD39 inhibition exhibiting potency in the low micromolar range, which is independent of substrate (ATP) concentration. We could show that ceritinib inhibits ATP dephosphorylation in peripheral blood mononuclear cells in a dose-dependent manner, resulting in a significant increase in ATP concentrations and preventing adenosine formation from ATP. Importantly, ceritinib (1-10 µM) substantially inhibited ATP hydrolysis in triple negative breast cancer and melanoma cells with high native expression of CD39.ConclusionsCD39 inhibition might contribute to the effects of the powerful anticancer drug ceritinib. Ceritinib is a novel CD39 inhibitor with high metabolic stability and optimized physicochemical properties; according to our knowledge, it is the first brain-permeant CD39 inhibitor. Our discovery will provide the basis (i) to develop more potent and balanced dual CD39/ALK inhibitors, and (ii) to optimize the ceritinib scaffold towards interaction with CD39 to obtain potent and selective drug-like CD39 inhibitors for future in vivo studies.

Dataset Information

Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor.

Publications

Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor.

Similar Datasets

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