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Drug Discovery → Target-Based

Target-based drug discovery relies on the selection of a single entity (protein/gene) relevant in the mechanism of disease. Although the target is chosen based on available evidence, the tractability and therapeutic relevance is monitored throughout the whole process. The risks associated with this pathway can be categorized as “validation risk”, the likelihood that modulation of the target will have a favorable outcome in patients, or “technical risks”, the likelihood that a tolerable molecule that modulates the target in patients can be discovered.

Target-based

  • Identifying a “druggable” biological target in the disease pathway
  • Well suited for diseases where a single gene mutation can be linked to the disease
  • Usual targets: primarily proteins (enzymes/receptors) but can also include DNA and RNA

  • Pharmacological assay must be chosen or created
  • Monitoring activity in isolated tissues from animals
  • Surrogate expression of human genes in cultured cells for large-scale exposure to chemicals

  • A high number of compounds can be screened against the target in a short amount of time
  • High-throughput screening of library of compounds

  • Around 50% of all “follower” drugs (also known as “me-too” drugs) are developed through this pathway
  • >90% failure rate in clinical trials for pioneer drugs due to lack of efficacy

Case Study: CCR5

HIV-1 entry is a multistep process. Binding of the HIV-1 envelope protein gp120 to the CD4 receptor on host cells is followed by engagement of specific chemokine receptors (CCR5 or CXCR4), leading to rearrangements in the envelope transmembrane subunit that result in membrane fusion.

The CCR5 co-receptor attracted considerable interest as a therapeutic target, as individuals with a natural mutation (CCR5–Δ32) that results in an absence of surface-expressed CCR5 have a high degree of resistance to HIV-1 infection, with no apparent significant adverse consequences.

Maraviroc is a selective CCR5 antagonist discovered through the medicinal chemistry optimization of a hit compound identified from high-throughput screening that prevents the interaction of HIV-1 gp120 and CCR5 that is necessary for CCR5-using (R5) HIV-1 to enter cells. Maraviroc is, to date, the only small molecule CC5R inhibitor in clinical use for the treatment of HIV-1 infection.

Reference for image: Haworth KG, Peterson CW, Kiem HP. CCR5-edited gene therapies for HIV cure: Closing the door to viral entry. Cytotherapy. 2017 Nov;19(11):1325-38.