Performance of GPScreen™
Drug target screening with GPScreen™ services are performed with genome-wide screening (using 4840 full mutant strains) of S. pombe heterozygous deletion mutant library.
Therefore, GPScreen™ provides Off (Toxicity)-targets as well as On (Efficacy)-targets of drug candidates precisely, thereby enabling drug target-based repositioning and rescuing very effectively.
Performance in drug target identification
In our study, GPScreen™ successfully determined the drug targets of existing anti-proliferative agents, which strongly indicates that this system can be effectively used for drug target identification of drug candidates under development.
More specifically, as shown in Figure 1, GPScreen™ identified act1, an S. pombe ortholog of human actin, as a target of cytochalasin A (A), and a PIK3, S. pombe ortholog of human PI3K, as a target of Wortmannin and Tor2 kinase (B).
Human actin is a well known target of cytochalasin A; PI3K, a target of Wortmannin and Tor2 kinase.
Figure 1. Performance of GPScreen™ in drug target identification
Performance in drug toxicity evaluation
In addition to drug target identification, GPScreen™ can be also used for drug toxicity evaluation.
Current toxicity evaluation systems have limitations to predict in-vivo toxicity by measuring only a small number of specific target-based in-vitro assays and animal-model-based organ toxicity.
Therefore, current drug toxicity evaluation systems are confronted with the increasing demand for genome-wide drug target profiling to assess drug toxicity more correctly.
To prove the performance of GPScreen™ in drug toxicity evaluation, we compared genome-wide drug target profiles of two commercial drugs with distinct in-vivo toxicity.
As shown in Figure 2, GPScreen™ provided highly relevant drug target profiles to the in-vivo toxicity of the tested compounds.
Considering the current situation of the absence of genome-wide drug target profiling systems, GPScreen™ will provide a breakthrough to lessen the drug R&D failure due to drug toxicity in clinical stages through assessing the drug toxicity from Off-targets at the early stages of drug discovery.
Furthermore, considering that drug toxicity is the one of the most serious problem in drug development, GPScreen will provide the more effective drug prioritization through genome-wide On/Off-target profiling at an early preclinical stages and change the drug R&D paradigm dramatically.
Figure 2. Performance of GPScreen™ in drug toxicity evaluation
(A) To verify the performance of GPScreen™ in drug toxicity evaluation,
we used two types of known drugs with distinct toxicity (Drug A; non-toxic compound which is now used in market, Drug B; a toxic compound which was withdrawn from market due to cardiotoxicity),
and investigated their genome-wide drug target profiles with GPScreen™ and compared the profiles each other in the respect of known in-vivo toxicity. (B) The promising drug targets of each compound as shown in blue/red-plotted areas in A were classified into their funtional groups.
In the results, a toxic compound 'Drug B' showed both more drug targets and more broad spectrum of target profile than those of a non-toxic compound 'Drug A' (Ba&Bb).