Off-target activity

In this chapter, the full BioPrint approach is described, as available from Cerep in terms of both the data set and the ability to have new compounds profiled and the results provided in the context of the BioPrint data set, including the known in vivo side effects of near neighbors in this biological space (see Section 2.5). The results for the differentiation of hit/lead compounds (see Section 2.3.2.1) sometimes use a subset of the 70-100 pharmacological assays that provide the maximum signal. Usually a decision on future work prioritization could be clearly made from the data from these subsets, saving time and money. For key reference/tool compounds, a full profile was used and is recommended to be used, as unexpected off-target activities may be found that cannot usually be predicted. 

Table 17.2 Off-target activities of cyclohexylglycine DPP-4 inhibitors (ICso s, nM).

Table 17.3 Potency and off-target activities of P-methyl phenyl-alanine-based DPP-4 inhibitors (IC50 s, nM).

Table 17.7 Potency and off-target activities of fused triazole derivatives.

Table 18.3 Control of log P to effect off-target activity at hERG. 

ALIS reports only compounds that bind directly to the target of interest, preventing false positives that arise from off-target activity or interactions with substrates or other reagents. Since ALIS directly identifies bound components by MS, the incidence of false positives based on bulk effects and non-specific binding is lower than that of biochemical assays that yield a secondary readout of activity. 

In addition to activity on a specific therapeutic target(s), most compounds have off-target activities. Human adverse effects are mainly due to these off-target activities. Therefore the entire activity profile, not just individual assay activities, is the preferred method to correlate in vitro activities and frequency of adverse effects. 

Class effects of drugs may be statistically associated both with the off-target activities and the desired therapeutic activities. 

Key words siRNA, Argonaute proteins, siRNA off-target activity, siRNA on-target activity, siRNA design, siRNA modifications... 

Avoiding siRNA Off- Target Activity by Experimental Design... 

---