Publications (2)4.8 Total impact
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Article: Discovery of a Plasmodium falciparum glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase inhibitor (R,Z)-N-((1-ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (ML276) that reduces parasite growth in vitro.
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ABSTRACT: A high-throughput screen of the NIH's MLSMR collection of ∼340000 compounds was undertaken to identify compounds that inhibit Plasmodium falciparum glucose-6-phosphate dehydrogenase (PfG6PD). PfG6PD is important for proliferating and propagating P. falciparum and differs structurally and mechanistically from the human orthologue. The reaction catalyzed by glucose-6-phosphate dehydrogenase (G6PD) is the first, rate-limiting step in the pentose phosphate pathway (PPP), a key metabolic pathway sustaining anabolic needs in reductive equivalents and synthetic materials in fast-growing cells. In P. falciparum , the bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (PfGluPho) catalyzes the first two steps of the PPP. Because P. falciparum and infected host red blood cells rely on accelerated glucose flux, they depend on the G6PD activity of PfGluPho. The lead compound identified from this effort, (R,Z)-N-((1-ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide, 11 (ML276), is a submicromolar inhibitor of PfG6PD (IC(50) = 889 nM). It is completely selective for the enzyme's human isoform, displays micromolar potency (IC(50) = 2.6 μM) against P. falciparum in culture, and has good drug-like properties, including high solubility and moderate microsomal stability. Studies testing the potential advantage of inhibiting PfG6PD in vivo are in progress.Journal of Medicinal Chemistry 07/2012; 55(16):7262-72. · 4.80 Impact Factor -
Chapter: Selective Bcl-2 Inhibitor Probes
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ABSTRACT: This probe report describes the identification and development of an inhibitor of Bcl-B, a member of the Bcl-2 family. The Bcl-2 family plays a prominent role in apoptosis. Bcl-2 is over-expressed in some cancers, allowing cells to continue proliferating. Thus, small molecule inhibitors of the anti-apoptotic Bcl-2 family members with their apoptotic partners would be useful for enhancing cancer chemotherapy. We developed a multiplexed bead-based flow cytometry high-throughput assay based on the disruption of the binding of a fluorescently labeled-BH3 peptide of Bim to the six anti-apoptotic Bcl-2 family members: Bcl-XL, Bcl-W, Bcl-B, Bfl-1, and Mcl-1 and Bcl-2 (the eponymous founding member of the Bcl-2 family). Using this assay, we screened each of 200,000 compounds in the NIH Molecular Libraries Small Molecule Repository (MLSMR) simultaneously (in multiplexed format) against all six Bcl-2 family members for potential regulators of these crucial peptide-protein interactions. We were able to develop a potent (368 nM IC50) inhibitor of the interaction of the Bim peptide with Bcl-B that was at least 127-fold selective over the Bim-Bcl-XL interaction. It was also shown to be selective against the other family members (Bcl-W, Bcl-2, Bfl-1, Mcl-1).
