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Gene-signature-derived IC50s/EC50s reflect the potency of causative upstream targets and downstream phenotypes

Renner, Steffen and Bergsdorf, Christian and Bouhelal, Rochdi and Koziczak-Holbro, Magdalena and Amati, Andrea Marco and Techer-Etienne, Valerie and FLOTTE, Ludivine and Reymann, Nicole and Kapur, Karen and Hoersch, Sebastian and Oakeley, Edward James and Schuffenhauer, Ansgar and Gubler, Hanspeter and Lounkine, Eugen and Farmer, Pierre (2020) Gene-signature-derived IC50s/EC50s reflect the potency of causative upstream targets and downstream phenotypes. Scientific reports, 10 (1). ISSN 2045-2322

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.

Item Type: Article
Date Deposited: 04 Jul 2020 00:45
Last Modified: 04 Jul 2020 00:45
URI: https://oak.novartis.com/id/eprint/40625

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