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Your search keyword '"Kovar PJ"' showing total 2 results
Start Over Author "Kovar PJ" Topic nicotinamide phosphoribosyltransferase
2 results on '"Kovar PJ"'

1. SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).

Author

Curtin ML, Heyman HR, Clark RF, Sorensen BK, Doherty GA, Hansen TM, Frey RR, Sarris KA, Aguirre AL, Shrestha A, Tu N, Woller K, Pliushchev MA, Sweis RF, Cheng M, Wilsbacher JL, Kovar PJ, Guo J, Cheng D, Longenecker KL, Raich D, Korepanova AV, Soni NB, Algire MA, Richardson PL, Marin VL, Badagnani I, Vasudevan A, Buchanan FG, Maag D, Chiang GG, Tse C, and Michaelides MR

Subjects
Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Proliferation drug effects, Crystallography, X-Ray, Cytokines chemistry, Cytokines metabolism, Drug Discovery, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors therapeutic use, Humans, Isoindoles chemistry, Isoindoles pharmacokinetics, Isoindoles pharmacology, Isoindoles therapeutic use, Mice, Models, Molecular, Neoplasms drug therapy, Neoplasms metabolism, Neoplasms pathology, Nicotinamide Phosphoribosyltransferase chemistry, Nicotinamide Phosphoribosyltransferase metabolism, Structure-Activity Relationship, Urea pharmacokinetics, Urea therapeutic use, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cytokines antagonists & inhibitors, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Nicotinamide Phosphoribosyltransferase antagonists & inhibitors, Urea analogs & derivatives, Urea pharmacology
Abstract

Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Published
2017
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2. Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors.

Author

Wilsbacher JL, Cheng M, Cheng D, Trammell SAJ, Shi Y, Guo J, Koeniger SL, Kovar PJ, He Y, Selvaraju S, Heyman HR, Sorensen BK, Clark RF, Hansen TM, Longenecker KL, Raich D, Korepanova AV, Cepa S, Towne DL, Abraham VC, Tang H, Richardson PL, McLoughlin SM, Badagnani I, Curtin ML, Michaelides MR, Maag D, Buchanan FG, Chiang GG, Gao W, Rosenberg SH, Brenner C, and Tse C

Subjects
Adenosine Triphosphate genetics, Adenosine Triphosphate metabolism, Animals, Calcium Signaling genetics, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Cytokines genetics, DNA Repair drug effects, Enzyme Activation drug effects, Gene Expression Regulation, Neoplastic drug effects, HCT116 Cells, Humans, Mice, NAD metabolism, Nicotinamide Phosphoribosyltransferase genetics, Xenograft Model Antitumor Assays, Colorectal Neoplasms drug therapy, Cytokines antagonists & inhibitors, Enzyme Inhibitors administration & dosage, Nicotinamide Phosphoribosyltransferase antagonists & inhibitors
Abstract

Cancer cells are highly reliant on NAD + -dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD + salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD + , and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD + depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236-45. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Published
2017
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