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Your search keyword '"Maliga Z"' showing total 2 results
Start Over Author "Maliga Z" Topic antineoplastic agents
2 results on '"Maliga Z"'

1. Hydrolysis of 2'3'-cGAMP by ENPP1 and design of nonhydrolyzable analogs.

Author

Li L, Yin Q, Kuss P, Maliga Z, Millán JL, Wu H, and Mitchison TJ

Subjects
Animals, Antineoplastic Agents chemical synthesis, Cell Line, Tumor, Humans, Hydrolysis, Interferon-beta, Membrane Proteins deficiency, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Monocytes drug effects, Monocytes metabolism, Monocytes pathology, Nucleotides, Cyclic chemistry, Nucleotides, Cyclic pharmacology, Organothiophosphorus Compounds chemical synthesis, Phosphoric Diester Hydrolases genetics, Phosphoric Diester Hydrolases metabolism, Pyrophosphatases genetics, Pyrophosphatases metabolism, Recombinant Proteins genetics, Recombinant Proteins metabolism, Second Messenger Systems genetics, Signal Transduction, Antineoplastic Agents pharmacology, Gene Expression Regulation, Neoplastic, Membrane Proteins agonists, Nucleotides, Cyclic metabolism, Organothiophosphorus Compounds pharmacology, Pyrophosphatases antagonists & inhibitors
Abstract

Agonists of mouse STING (TMEM173) shrink and even cure solid tumors by activating innate immunity; human STING (hSTING) agonists are needed to test this therapeutic hypothesis in humans. The endogenous STING agonist is 2'3'-cGAMP, a second messenger that signals the presence of cytosolic double-stranded DNA. We report activity-guided partial purification and identification of ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) to be the dominant 2'3'-cGAMP hydrolyzing activity in cultured cells. The hydrolysis activity of ENPP1 was confirmed using recombinant protein and was depleted in tissue extracts and plasma from Enpp1(-/-) mice. We synthesized a hydrolysis-resistant bisphosphothioate analog of 2'3'-cGAMP (2'3'-cG(s)A(s)MP) that has similar affinity for hSTING in vitro and is ten times more potent at inducing IFN-β secretion from human THP1 monocytes. Studies in mouse Enpp1(-/-) lung fibroblasts indicate that resistance to hydrolysis contributes substantially to its higher potency. 2'3'-cG(s)A(s)MP is therefore improved over natural 2'3'-cGAMP as a model agonist and has potential as a vaccine adjuvant and cancer therapeutic.

Published
2014
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2. Anticancer flavonoids are mouse-selective STING agonists.

Author

Kim S, Li L, Maliga Z, Yin Q, Wu H, and Mitchison TJ

Subjects
Animals, Humans, Immunity, Innate drug effects, Membrane Proteins metabolism, Mice, Molecular Targeted Therapy, Protein Binding, Structure-Activity Relationship, Xanthones pharmacology, Antineoplastic Agents pharmacology, Flavonoids pharmacology, Membrane Proteins agonists
Abstract

The flavonoids FAA and DMXAA showed impressive activity against solid tumors in mice but failed clinical trials. They act on a previously unknown molecular target(s) to trigger cytokine release from leukocytes, which causes tumor-specific vascular damage and other antitumor effects. We show that DMXAA is a competitive agonist ligand for mouse STING (stimulator of interferon genes), a receptor for the bacterial PAMP cyclic-di-GMP (c-di-GMP) and an endogenous second messenger cyclic-GMP-AMP. In our structure-activity relationship studies, STING binding affinity and pathway activation activity of four flavonoids correlated with activity in a mouse tumor model measured previously. We propose that STING agonist activity accounts for the antitumor effects of FAA and DMXAA in mice. Importantly, DMXAA does not bind to human STING, which may account for its lack of efficacy or mechanism-related toxicity in man. We propose that STING is a druggable target for a novel innate immune activation mechanism of chemotherapy.

Published
2013
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