Opportunities and challenges in phenotypic drug discovery: an industry perspective

@article{Moffat2017OpportunitiesAC,
  title={Opportunities and challenges in phenotypic drug discovery: an industry perspective},
  author={John G. Moffat and Fabien Vincent and Jonathan A. Lee and J{\"o}rg Eder and Marco Prunotto},
  journal={Nature Reviews Drug Discovery},
  year={2017},
  volume={16},
  pages={531-543}
}
Phenotypic drug discovery (PDD) approaches do not rely on knowledge of the identity of a specific drug target or a hypothesis about its role in disease, in contrast to the target-based strategies that have been widely used in the pharmaceutical industry in the past three decades. However, in recent years, there has been a resurgence in interest in PDD approaches based on their potential to address the incompletely understood complexity of diseases and their promise of delivering first-in-class… Expand
Recent advances in phenotypic drug discovery
TLDR
In this short review, recent advances are noted for the implementation and de-risking of PDD (for compound library selection, biomarker development, mechanism identification, and safety studies) and the potential for artificial intelligence. Expand
The future of phenotypic drug discovery.
  • E. Berg
  • Medicine
  • Cell chemical biology
  • 2021
TLDR
How human-based phenotypic platforms are being applied throughout the discovery process for hit triage and prioritization, for elimination of hits with unsuitable mechanisms, and for supporting clinical strategies through pathway-based decision frameworks are discussed. Expand
Filling the drug discovery gap: is high-content screening the missing link?
TLDR
Progress in High-Content Screening technology has also contributed to the recent excitement for phenotypic drug discovery approaches, bringing image-capture and processing, and data-analysis, to a level of content and throughput fully compatible with large scale drug discovery efforts. Expand
Exploring different approaches to improve the success of drug discovery and development projects: a review
There has been a significant increase in the cost and timeline of delivering new drugs for clinical use over the last three decades. Despite the increased investments in research infrastructure byExpand
High-content phenotypic and pathway profiling to advance drug discovery in diseases of unmet need.
TLDR
This review provides an overview of how emerging phenotypic and pathway-profiling technologies integrate to deconvolute the mechanism-of-action of Phenotypic hits and proposes that such in-depth mechanistic profiling may support more efficient phenotypesic drug discovery strategies that are designed to more appropriately address complex heterogeneous diseases of unmet need. Expand
Use of artificial intelligence to enhance phenotypic drug discovery.
TLDR
The potential of target-driven and phenotypic-based approaches are assessed and a holistic description of the current state of the field is offered, from both a scientific and industry perspective. Expand
Direct and indirect approaches to identify drug modes of action
TLDR
This review looks at some of the recent developments in the identification of drug modes of action, focusing on phenotype‐based methods using metabolomics, proteomics, transcriptomics, and genomics to detect changes in phenotype in response to the presence of the drug, and affinity‐ based methods using modified/unmodified drug as bait to capture and identify targets. Expand
The right tools for the job: the central role for next generation chemical probes and chemistry-based target deconvolution methods in phenotypic drug discovery
TLDR
The current capabilities of chemical probes and chemistry-based target deconvolution methods are discussed and the next advances necessary in order to fully support phenotypic screening approaches in drug discovery are evaluated. Expand
A New Drug Discovery Approach Based on Thermal Proteome Profiling to Develop More Effective Drugs
: The search for disease-related targets and studying drug-protein and protein-protein interactions are central issues that would accelerate the clinical approval of a drug. Also, by developing anExpand
The Impact of Chemical Biology on Drug Discovery
In early times, the drug discovery process was mainly based on profiling of new medications in in vivo systems. In the absence of knowledge on enzymatic structures, biochemical signaling or preciseExpand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 147 REFERENCES
Phenotypic screening in cancer drug discovery — past, present and future
TLDR
It is postulate that the contribution of phenotypic screening to cancer drug discovery has been hampered by a reliance on 'classical' nonspecific drug effects such as cytotoxicity and mitotic arrest, exacerbated by a paucity of mechanistically defined cellular models for therapeutically translatable cancer phenotypes. Expand
Functional genomics to uncover drug mechanism of action.
  • S. Nijman
  • Biology, Medicine
  • Nature chemical biology
  • 2015
TLDR
Recently developed functional genomics technologies that address this need are reviewed and the approaches pioneered in model organisms, particularly in yeast, and more recently adapted to mammalian systems are discussed. Expand
How were new medicines discovered?
TLDR
It is postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development. Expand
A comprehensive map of molecular drug targets
TLDR
An updated comprehensive map of molecular targets of approved drugs is presented and the relationships between bioactivity class and clinical success, as well as the presence of orthologues between human and animal models and between pathogen and human genomes are explored. Expand
Screening out irrelevant cell-based models of disease
TLDR
A set of principles to facilitate the definition and development of disease-relevant assays is proposed and new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery are discussed, including induced pluripotent stem cells, threeD co-culture and organ-on-a-chip systems. Expand
The discovery of first-in-class drugs: origins and evolution
TLDR
An analysis of the origins of all 113 first-in-class drugs approved by the FDA from 1999 to 2013 shows that the majority (78) were discovered through target-based approaches (45 small-molecule drugs and 33 biologics), with the implications for drug discovery strategies, including viewing phenotypic screening as a novel discipline rather than as a neoclassical approach. Expand
The Power of Sophisticated Phenotypic Screening and Modern Mechanism-of-Action Methods.
TLDR
Recent advances in phenotypic readouts and MoA determination are highlighted by discussing several case studies in which both activities were required for understanding the chemical biology involved and, in some cases, advancing toward clinical development. Expand
Drug discovery: a historical perspective.
TLDR
The biotech industry is establishing itself as the discovery arm of the pharmaceutical industry, and in bridging the gap between academia and large pharmaceutical companies, the biotech firms have been effective instruments of technology transfer. Expand
Polypharmacology in Drug Discovery: A Review from Systems Pharmacology Perspective.
TLDR
A global view on polypharmacology is provided, which is the foundation of the next paradigm in drug discovery, and some computational methods to predict the potential novel multi-target drugs with lower toxicity and higher efficacy are presented. Expand
Functional Genomics in Pharmaceutical Drug Discovery.
TLDR
RNAi is discussed with its advantages and challenges and the potential of CRISPR/Cas9, a gene-editing method that has recently been adapted for use as functional screening tool, will be briefly reviewed. Expand
...
1
2
3
4
5
...