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Start Over Author "Cross JB" Journal bioorganic medicinal chemistry letters
3 results on '"Cross JB"'

1. Structure-based discovery of LpxC inhibitors.

Author

Zhang J, Chan A, Lippa B, Cross JB, Liu C, Yin N, Romero JA, Lawrence J, Heney R, Herradura P, Goss J, Clark C, Abel C, Zhang Y, Poutsiaka KM, Epie F, Conrad M, Mahamoon A, Nguyen K, Chavan A, Clark E, Li TC, Cheng RK, Wood M, Andersen OA, Brooks M, Kwong J, Barker J, Parr IB, Gu Y, Ryan MD, Coleman S, and Metcalf CA 3rd

Subjects
Amidohydrolases metabolism, Drug Discovery, Gram-Negative Bacterial Infections drug therapy, Humans, Molecular Docking Simulation, Amidohydrolases antagonists & inhibitors, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Gram-Negative Bacteria drug effects, Gram-Negative Bacteria enzymology
Abstract

The emergence and spread of multidrug-resistant (MDR) Gram negative bacteria presents a serious threat for public health. Novel antimicrobials that could overcome the resistance problems are urgently needed. UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) is a cytosolic zinc-based deacetylase that catalyzes the first committed step in the biosynthesis of lipid A, which is essential for the survival of Gram-negative bacteria. Our efforts toward the discovery of novel LpxC inhibitors are presented herein., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Published
2017
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2. Identification of potent and selective MTH1 inhibitors.

Author

Petrocchi A, Leo E, Reyna NJ, Hamilton MM, Shi X, Parker CA, Mseeh F, Bardenhagen JP, Leonard P, Cross JB, Huang S, Jiang Y, Cardozo M, Draetta G, Marszalek JR, Toniatti C, Jones P, and Lewis RT

Subjects
DNA Repair Enzymes metabolism, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Models, Molecular, Molecular Structure, Phosphoric Monoester Hydrolases metabolism, Structure-Activity Relationship, Substrate Specificity, DNA Repair Enzymes antagonists & inhibitors, Enzyme Inhibitors pharmacology, Phosphoric Monoester Hydrolases antagonists & inhibitors
Abstract

Structure based design of a novel class of aminopyrimidine MTH1 (MutT homolog 1) inhibitors is described. Optimization led to identification of IACS-4759 (compound 5), a sub-nanomolar inhibitor of MTH1 with excellent cell permeability and good metabolic stability in microsomes. This compound robustly inhibited MTH1 activity in cells and proved to be an excellent tool for interrogation of the utility of MTH1 inhibition in the context of oncology., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Published
2016
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3. Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB.

Author

Mesleh MF, Cross JB, Zhang J, Kahmann J, Andersen OA, Barker J, Cheng RK, Felicetti B, Wood M, Hadfield AT, Scheich C, Moy TI, Yang Q, Shotwell J, Nguyen K, Lippa B, Dolle R, and Ryan MD

Subjects
Adenosine Triphosphatases metabolism, Anti-Bacterial Agents metabolism, Bacterial Proteins metabolism, Binding Sites, Crystallography, X-Ray, DNA Gyrase metabolism, DNA Topoisomerase IV antagonists & inhibitors, DNA Topoisomerase IV metabolism, Drug Design, Escherichia coli metabolism, Ligands, Magnetic Resonance Spectroscopy, Molecular Dynamics Simulation, Protein Binding, Protein Structure, Tertiary, Staphylococcus aureus enzymology, Topoisomerase II Inhibitors metabolism, Anti-Bacterial Agents chemistry, Bacterial Proteins antagonists & inhibitors, DNA Gyrase chemistry, Topoisomerase II Inhibitors chemistry
Abstract

Inhibitors of the ATPase function of bacterial DNA gyrase, located in the GyrB subunit and its related ParE subunit in topoisomerase IV, have demonstrated antibacterial activity. In this study we describe an NMR fragment-based screening effort targeting Staphylococcus aureus GyrB that identified several attractive and novel starting points with good ligand efficiency. Fragment hits were further characterized using NMR binding studies against full-length S. aureus GyrB and Escherichia coli ParE. X-ray co-crystal structures of select fragment hits confirmed binding and suggested a path for medicinal chemistry optimization. The identification, characterization, and elaboration of one of these fragment series to a 0.265 μM inhibitor is described herein., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Published
2016
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