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1.
Sci Rep ; 10(1): 9670, 2020 06 15.
Article in English | MEDLINE | ID: mdl-32541899

ABSTRACT

Multiplexed gene-signature-based phenotypic assays are increasingly used for the identification and profiling of small molecule-tool compounds and drugs. Here we introduce a method (provided as R-package) for the quantification of the dose-response potency of a gene-signature as EC50 and IC50 values. Two signaling pathways were used as models to validate our methods: beta-adrenergic agonistic activity on cAMP generation (dedicated dataset generated for this study) and EGFR inhibitory effect on cancer cell viability. In both cases, potencies derived from multi-gene expression data were highly correlated with orthogonal potencies derived from cAMP and cell growth readouts, and superior to potencies derived from single individual genes. Based on our results we propose gene-signature potencies as a novel valid alternative for the quantitative prioritization, optimization and development of novel drugs.


Subject(s)
Adrenergic beta-Agonists/pharmacology , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/drug effects , Neoplasms/genetics , Adrenergic beta-Agonists/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclic AMP/metabolism , Dose-Response Relationship, Drug , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Humans , Inhibitory Concentration 50 , Neoplasms/drug therapy , Neoplasms/metabolism , Phenotype , Signal Transduction/drug effects , THP-1 Cells
2.
J Pharmacol Exp Ther ; 369(2): 188-199, 2019 05.
Article in English | MEDLINE | ID: mdl-30819762

ABSTRACT

The anabolic effects of ß 2-adrenoceptor (ß 2-AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of ß 2-AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived ß 2-AR agonist in comparison with formoterol as a representative ß 2-AR agonist that have been well characterized. In vitro, 5-HOB has nanomolar affinity for the human ß 2-AR and selectivity over the ß 1-AR and ß 3-AR. 5-HOB also shows potent agonistic activity at the ß 2-AR in primary skeletal muscle myotubes and induces hypertrophy of skeletal muscle myotubes. Compared with formoterol, 5-HOB demonstrates comparable full-agonist activity on cAMP production in skeletal muscle cells and skeletal muscle tissue-derived membranes. In contrast, a greatly reduced intrinsic activity was determined in cardiomyocytes and cell membranes prepared from the rat heart. In addition, 5-HOB shows weak effects on chronotropy, inotropy, and vascular relaxation compared with formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats with attenuated effects on heart weight and ejection fraction, unlike formoterol. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB compared with formoterol. In conclusion, the pharmacological profile of 5-HOB indicates superior tissue selectivity compared with the conventional ß 2-AR agonist formoterol in preclinical studies and supports the notion that such tissue-selective agonists should be investigated for the safe treatment of muscle-wasting conditions without cardiovascular limiting effects.


Subject(s)
Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Cardiovascular System/drug effects , Muscle, Skeletal/drug effects , Receptors, Adrenergic, beta-2/metabolism , Safety , Adrenergic beta-2 Receptor Agonists/adverse effects , Adrenergic beta-2 Receptor Agonists/chemistry , Adrenergic beta-2 Receptor Agonists/pharmacology , Adrenergic beta-2 Receptor Agonists/therapeutic use , Anabolic Agents/adverse effects , Anabolic Agents/chemistry , Anabolic Agents/pharmacology , Anabolic Agents/therapeutic use , Animals , Benzothiazoles/adverse effects , Benzothiazoles/therapeutic use , CHO Cells , Cricetulus , Heart/drug effects , Humans , Hypertrophy/drug therapy , Kinetics , Macaca mulatta , Male , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Myocytes, Cardiac/drug effects , Rats
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