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3 results on '"Tom Wisniewski"'

1. Label-free LC-MS based assay to characterize small molecule compound binding to cells

Author

Menglin Chen, Zhengrong Zhu, Tom Wisniewski, Xiaoping Zhang, David G. McLaren, Adam Weinglass, and S. Adrian Saldanha

Subjects
Label-free technologies, LC-MS, Cell-based assays, Affinity binding, Medicine (General), R5-920, Biotechnology, TP248.13-248.65
Abstract

Study of small molecule binding to live cells provides important information on the characterization of ligands pharmacologically. Here we developed and validated a label-free, liquid chromatography-mass spectrometry (LC-MS) based cell binding assay, using centrifugation to separate binders from non-binders. This assay was applied to various target classes, with particular emphasis on those for which protein-based binding assay can be difficult to achieve. In one example, to study a G protein coupled receptor (GPCR), we used one antagonist as probe and multiple other antagonists as competitor ligands. Binding of the probe was confirmed to be specific and saturable, reaching a fast equilibrium. Competition binding analysis by titration of five known ligands suggested a good correlation with their inhibition potency. In another example, this assay was applied to an ion channel target with its agonists, of which the determined binding affinity was consistent with functional assays. This versatile method allows quantitative characterization of ligand binding to cell surface expressed targets in a physiologically relevant environment.

Published
2022
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2. Discovery of Triazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys

Author

Chris J. van Koppen, Scott B. Hoyt, Gino Salituro, Elaine Tung, Jim Tata, Joe Clemas, Mark Rosenbach, Jack Gibson, Daphne Szeto, Wei Tang, Andreas Verras, Lee-Yuh Pai, Ning Ren, Carrie Ann Maxwell, Joe Metzger, Jose Castro-Perez, Qing Chen, Lina Yin, Daniel R. McMasters, Yusheng Xiong, Rolf W. Hartmann, Mary Struthers, Gui-Bai Liang, Charlene Bopp, Xiuying Ma, Gaochao Zhou, Richard Hajdu, Tom Wisniewski, Mike E. Lassman, Nicole Buist, Clare London, Andrea Sok, Gail Forrest, Sloan Stribling, Theresa McLaughlin, Qingzhong Hu, Tian-Quan Cai, and Whitney Lane Petrilli

Subjects
Aldosterone synthase, medicine.medical_specialty, Aldosterone, Organic Chemistry, Triazole, Hit to lead, Biology, Pharmacology, Biochemistry, chemistry.chemical_compound, Endocrinology, chemistry, Pharmacokinetics, In vivo, Pharmacodynamics, Internal medicine, Drug Discovery, medicine, biology.protein, Cortisol level
Abstract

Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

Published
2015

3. Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys

Author

Daphne Szeto, Doris F. Cully, Scott B. Hoyt, Ning Ren, Elaine Tung, Charlene Bopp, Jack Gibson, Gino Salituro, Clare London, Jiaqiang Cai, Amjad Ali, Qing Chen, Andrea Sok, Simone Belshaw, Carrie Ann Maxwell, Mark Rosenbach, Gaochao Zhou, Gail Forrest, Tian-Quan Cai, Daniel R. McMasters, Lee-Yuh Pai, Nelo R. Rivera, Sloan Stribling, Emma Carswell, Richard Hajdu, Robinson John E, Andrew J. Cooke, Jeff Kuethe, Tom Wisniewski, Joe Metzger, Thomas R. Clarkson, Gui-Bai Liang, Mary Struthers, Jim Tata, Mike E. Lassman, Lindsay Brown, Wei Tang, Theresa McLaughlin, Xiuying Ma, Nicole Buist, Kun Liu, Joe Clemas, D. Jonathan Bennett, Andreas Verras, Min K. Park, Yusheng Xiong, John Maclean, and Jose Castro-Perez

Subjects
Aldosterone synthase, Benzimidazole, medicine.medical_specialty, Aldosterone, Organic Chemistry, High selectivity, Biology, Pharmacology, Biochemistry, chemistry.chemical_compound, Endocrinology, chemistry, Pharmacokinetics, In vivo, Internal medicine, Pharmacodynamics, Drug Discovery, medicine, biology.protein, Cortisol level
Abstract

We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

Published
2015

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