How were new medicines discovered?

@article{Swinney2011HowWN,
  title={How were new medicines discovered?},
  author={David C. Swinney and Jason Anthony},
  journal={Nature Reviews Drug Discovery},
  year={2011},
  volume={10},
  pages={507-519}
}
  • D. SwinneyJ. Anthony
  • Published 1 July 2011
  • Biology, Chemistry, Medicine
  • Nature Reviews Drug Discovery
Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. [] Key Method To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between…

The discovery of first-in-class drugs: origins and evolution

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.

The Contribution of Mechanistic Understanding to Phenotypic Screening for First-in-Class Medicines

  • D. Swinney
  • Biology, Chemistry
    Journal of biomolecular screening
  • 2013
The format and mechanistic information used to establish the phenotypic assays that led to the first-in-class small-molecule new molecular entities approved by the U.S. Food and Drug Administration between 1999 and 2008 were analyzed and compared with those approved in 2012 and concluded that mechanism takes on different connotations depending on context and perspective.

Phenotypic screening in cancer drug discovery — past, present and future

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.

The Oncopig Cancer Model as a Complementary Tool for Phenotypic Drug Discovery

A mini-review on the reemergence of PDD in drug development is provided, highlighting the potential of porcine cancer models for improving pre-clinical drug discovery and testing and the precision medicine based genetically defined swinecancer models developed to date and their potential as biomedical models.

Target identification of small molecules based on chemical biology approaches.

Recent progress in both affinity-based (direct) and phenotypic profiling (indirect) approaches for chemical biology target identification are described and summarized.

A comprehensive map of molecular drug targets

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.

Cell-Based Phenotypic Approaches in Drug Discovery

The value of large-scale human cell-based phenotypic profiling for incorporating human-specific biology into the de-risking process and how Adverse Outcome Pathway frameworks can be used to integrate results from diverse platforms congruent with weight-of-evidence approaches from risk assessment to improve safety-related decisions in early discovery are discussed.

Next Generation Phenotypic Screening : Part of a balanced strategy for accelerating drug discovery

  • Biology
  • 2014
Technology innovations were crucial to the shift from phenotypic to target-based discovery and will again be important in enabling this newly emerging balanced strategy.

Identifying mechanism-of-action targets for drugs and probes

Using a chemoinformatics approach, drugs that lack primary targets are “de-orphanize” and chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology.
...

References

SHOWING 1-10 OF 197 REFERENCES

Phenotypic screening strategies for neurodegenerative diseases: a pathway to discover novel drug candidates and potential disease targets or mechanisms.

  • R. Pruss
  • Biology
    CNS & neurological disorders drug targets
  • 2010
The establishment of phenotypic screening assays using primary neurons subjected to a disease-relevant pathophysiological stress and measuring the most important functional outcome, survival are described.

Rethinking target discovery in polygenic diseases.

The limitations of current molecular target discovery approaches mainly in regard to selectivity and efficacy are discussed and how the reconsideration of molecular and clinical targets in polygenic diseases may lead to new strategies of pharmacological intervention directed against component dysfunctions is described.

How many drug targets are there?

A consensus number of current drug targets for all classes of approved therapeutic drugs is proposed, and an emerging realization of the importance of polypharmacology and also the power of a gene-family-led approach in generating novel and important therapies is highlighted.

Transcript profiling and RNA interference as tools to identify small molecule mechanisms and therapeutic potential.

This Review highlights recent successes in using pattern matching and chemical genetic tools, with the goal of uncovering small molecule mechanisms and identifying therapeutic candidates for disease treatment.

Probing the links between in vitro potency, ADMET and physicochemical parameters

Key findings include: first, that oral drugs seldom possess nanomolar potency; second, that many oral drugs have considerable off-target activity; and third, that in vitro potency does not correlate strongly with the therapeutic dose.

Strategies for discovering and derisking covalent, irreversible enzyme inhibitors.

This article presents several covalent inhibitors, including examples of successful drugs, as well as highly selective, irreversible inhibitors of emerging therapeutic targets, such as fatty acid

Natural products as sources of new drugs over the last 25 years.

This review is an updated and expanded version of two prior reviews that were published in this journal in 1997 and 2003 and is able to identify only one de novo combinatorial compound approved as a drug in this 25 plus year time frame.

Target discovery

  • M. Lindsay
  • Biology
    Nature Reviews Drug Discovery
  • 2003
The likely impact of recent technological advances, including genomics, proteomics, small interfering RNA and mouse knockout models, are examined, and the likelihood of future trends is speculated on.
...