An analysis was completed of ~1300 diverse drug discovery project compounds which were tested against a panel of 125 off-target receptors. For each target, hit-rates were calculated (categories of IC50&lt;10 μM and IC50&lt;2 μM), along with the average calculated logD (clogD), molecular weight (MW) and ionization classification of the hit compound sets. These properties were also compared against the inactive compounds for each receptor. Some receptors demonstrated very high hit-rates. For example, 38% of the compounds tested in an adenosine transporter assay demonstrated an IC50 &lt;10 μM using a 3[H] nitrobenzylthioinosine binding assay. In comparison, some off-target assays did not demonstrate hits for any of the compounds tested (e.g. GABA-B binding, H2 cAMP functional assay). Of the 125 targets in the panel, an analysis of the “hits” versus “inactives” demonstrated the vast majority (&gt;90%) of targets favored higher logD, higher MW, and more basic compounds than inactives in each set. Finally, an assessment of off-target profiles of recent clinical candidates which successfully passed Phase 1 safety studies illustrated that most successful Phase 1 clinical candidates only have a small number of off-target hits, but there are significant exceptions to this observation which will be discussed. Overall, this analysis has been useful in building a better understanding of common off-target and secondary pharmacological risks in lead optimization programs, as well as strategies which help to mitigate these risks.

Assessment of AstraZeneca secondary pharmacology profiling assays and applications to lead optimization efforts

256th National Meeting (2018)

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