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 critical ‘oncogene addiction’ 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.
Taken to its logical extension; 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. Moreover, 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.
Click on the image to enlarge.
Two candidates were shown to have a significant therapeutic window and one was safe in active doses in-vivo (see below) and was investigated further by a big Pharma company.
Click on the image to enlarge.
Additional data-sets are available for each application and can be shared under confidential disclosure agreement. Please write to info@horizondiscovery.com for details
Horizon Offering
Horizon Discovery has a wide range of isogenic models available for immediate licensing or purchasing (Learn more) and; can also develop custom isogenic models or screen drug candidates against your specific gene target (Learn more)
References
- Torrance et al, Nature Biotechnology, 2001
- Horizon Discovery Ltd. Technical Presentation (Download)
