Mechanisms of Skin Toxicity Associated with Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators

Literature buzz Life Science

Decrypting skin toxicity responses induced by CNS drug treatment

Expert opinion

When developing new drugs, one of the many equations pharmacologists need to resolve during pre-clinical and clinical stages is that regarding the added value of drug treatment versus potential side effects. Drug-induced side effects may be mild, while others are simply an inconvenience. On the other hand, some side effects can be serious or even life-threatening for patients. Safety assessments are key milestones during drug development, including studies covering toxicity characterization, tolerance, and complete understanding of drug metabolism and drug interaction. The safety factor represents a high risk of go/no-go as well as a source of attrition for drug candidates.
Metabotropic glutamate receptor 5 Negative Allosteric Modulators (mGluR5 NAM) represent a very popular and attractive approach for identifying new treatments for several neurological disorders and potentially addiction. Many NAMs are in the pre-clinical or clinical stages of the drug candidate pipeline. However, showing no exception to the rule, some candidates failed during development due to severe side effects. This is the end of the story for any given drug candidate, but it also represents a new start for scientists’ understanding of the mechanisms of action (MoA) underlying unexpected side effects, often opening an opportunity to define a new drug development strategy.
A detailed investigation of the molecular mechanisms leading to mGluR5-NAM induced skin toxicity is presented in this article published by Falgun Shah.
A set of compounds belonging to the same chemical series as a candidate that failed during preclinical development was studied thoroughly and profiled on a panel of primary human cell-based assays. Inflammation-related and immunomodulatory activities were fully assessed for each of them in phenotypic studies (BioMAP profiles).
Elevation of PGE2 (through an agonism effect) and increase of IL-6 and IL-2 production (through an antagonism effect) are the first cellular events triggered by mGluR5-NAMs. Both lead to induced skin toxicity through specific pathways.
Understanding how your drug induces side effects at the cellular or molecular level is critical for limiting drug attrition as well as for fine-tuning your development strategy. Seeking the optimal risk-benefit balance for your candidate is key. It is always better for you to have the complete picture and full understanding of its MoA.

Abstract

Cutaneous reactions represent one of the most common adverse drug effects observed in clinical trials leading to substantial compound attrition. Three negative allosteric modulators (NAMs) of metabotropic glutamate receptors (mGluRs), which represent an important target for neurological diseases, developed by Pfizer, were recently failed in preclinical development due to delayed type IV skin hypersensitivity observed in non-human primates (NHPs). Here we employed large-scale phenotypic profiling in standardized panels of human primary cell/co-culture systems to characterize the skin toxicity mechanism(s) of mGluR5 NAMs from two different series. Investigation of a database of chemicals tested in these systems and transcriptional profiling suggested that the mechanism of toxicity may involve modulation of nuclear receptor targets RAR/RXR, and/or VDR with AhR antagonism. The studies reported here demonstrate how phenotypic profiling of preclinical drug candidates using human primary cells can provide insights into the mechanisms of toxicity and inform early drug discovery and development campaigns.

Details

Cell Chemical Biology. 2017 Jul 20;24(7):858-869.

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