Applications

Drug Screening

In modern day drug discovery there is a particular need to understand: (a) when to optimise a candidate drug against a specific target and (b) for how long this optimisation process should continue before entering animal and human trials.

A candidate drug is sufficiently developed when it displays potent and selective effects on cells harbouring a specific genetic situation that is highly-relevant to the disease vs. normalised state. However such information has been hard to come by and has led to ambiguous and needlessly protracted drug development pipelines.

Isogenic tumour vs. normal cell-line pairs can be readily used in multiplexed assay formats and/or automated HTS screening regimes to enable users to rationally generate more compounds with a greater chance of success in later stages of drug development.

Screening large compound libraries directly against these models for novel patient-relevant drug-candidates or optimal therapeutic combinations, has the potential for bringing massive savings in time and cost associated with discovering targeted cancer agents. Isogenic models are directly compatible with legacy cell-based screening reagents, automation detection and informatics technologies and can thus be slotted into existing screening regimes.

An example of this strategy is given below, showing a drug-candidate isolated from a screen of 30,000 compounds that displays selective activity for cancer cells harbouring a mutant form the signalling protein ‘K-Ras’; which has so far eluded conventional discovery pipelines.

Compound Profiling
K-RAS Dose Response

References
  • Torrance et al, patent pending, 2003
  • Vogelstein et al, patents pending, 2001/02
  • Torrance et al, Nature Biotechnology, 2001 [Download]

See also:

Relevant data-sets are available for each application and can be shared under confidential disclosure agreement. Please write to info@horizondiscovery.com for details