Gene-signature-derived IC 50 s/EC 50 s reflect the potency of causative upstream targets and downstream phenotypes.

Autor:	Renner S; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research (NIBR), Basel, 4056, Switzerland. steffen.renner@novartis.com., Bergsdorf C; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research (NIBR), Basel, 4056, Switzerland., Bouhelal R; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research (NIBR), Basel, 4056, Switzerland., Koziczak-Holbro M; Musculoskeletal, NIBR, Basel, Switzerland., Amati AM; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research (NIBR), Basel, 4056, Switzerland.; Department of Chemistry & Biochemistry, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland., Techer-Etienne V; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research (NIBR), Basel, 4056, Switzerland., Flotte L; Musculoskeletal, NIBR, Basel, Switzerland., Reymann N; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research (NIBR), Basel, 4056, Switzerland., Kapur K; NIBR Informatics, NIBR, Basel, Switzerland., Hoersch S; NIBR Informatics, NIBR, Basel, Switzerland., Oakeley EJ; ASI, NIBR, Basel, Switzerland., Schuffenhauer A; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research (NIBR), Basel, 4056, Switzerland., Gubler H; NIBR Informatics, NIBR, Basel, Switzerland., Lounkine E; Chemical Biology & Therapeutics, NIBR, 181 Massachusetts Avenue, Cambridge, MA, 02139, USA.; Modeling and Informatics, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA, 02115, USA., Farmer P; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research (NIBR), Basel, 4056, Switzerland. pierre.farmer@novartis.com.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2020 Jun 15; Vol. 10 (1), pp. 9670. Date of Electronic Publication: 2020 Jun 15.
DOI:	10.1038/s41598-020-66533-5
Abstrakt:	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 EC 50 and IC 50 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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu Plný text ve formátu PDF