Gene-signature-derived ICs/ECs reflect the potency of causative upstream targets and downstream phenotypes.

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 and IC 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.

A High-Throughput Screening Identifies MICU1 Targeting Compounds.

Mitochondrial Ca uptake depends on the mitochondrial calcium uniporter (MCU) complex, a highly selective channel of the inner mitochondrial membrane (IMM). Here, we screen a library of 44,000 non-proprietary compounds for their ability to modulate mitochondrial Ca uptake. Two of them, named MCU-i4 and MCU-i11, are confirmed to reliably decrease mitochondrial Ca influx.

In vitro safety pharmacology profiling: what else beyond hERG?

One of the main reasons for drug failures in clinical development, or postmarket launch, is lacking or compromised safety margins at therapeutic doses. Organ toxicity with poorly defined mechanisms and adverse drug reactions associated with on- and off-target effects are the major contributors to safety-related shortfalls of many clinical drug candidates. Therefore, to avoid high attrition rates in clinical trials, it is imperative to test compounds for potential adverse reactions during early drug discovery.