Drug Discovery
Figure 1
observed during Phase II-III studies, offsetting some of the HTS benefits4.
Changing the drug discovery paradigm The overall efficiency of pharmaceutical research and development (R&D), defined as the ratio of the New Molecular Entities (NMEs) and Biologic License Applications (BLAs) launched as a func- tion of their associated R&D investments, has declined over the last decade5. To improve the sit- uation, numerous advances were brought to the drug discovery process. For instance, predictive toxicology concepts
were introduced during absorption, distribution, metabolism, elimination and toxicity (ADMET) to fail drug candidates more rapidly and reduce the drug attrition rate related to safety. While toxicity was traditionally assessed using animal models during the late stage of drug development, predic- tive toxicology required the development of in sili- co and in vitro methods executable at large scale and sooner in the drug discovery workflow. In sil- ico methods essentially involve quantitative struc- ture activity relationships (QSAR) where potential- ly toxic compounds are filtered out from libraries based on their structure. In vitro assays rely on specialised cell lines (eg hepatocytes for liver toxic- ity), microscale physiological systems (eg organ- on-a-chip) and small animal models (eg zebrafish, C.elegans, etc). It is worth mentioning that both European Union and North American agencies
10
spearheaded large scale predictive toxicology pro- grammes, such as EU-ToxRisk and EPA- ToxCast/Tox21 respectively. To further decrease the compound attrition rate due to lack of efficacy, scientists moved from a target-based approach to a phenotypic strategy where assays take advantage of more biologically-relevant models, including mono- or co-cultured cells, organoids and small animal models such as those described previously. HTS campaigns are also performed using smaller and more focused libraries composed of a few hun- dred thousand compounds pre-assembled using QSAR. Chemistry efforts to expand the actual druggable chemical space are under way to better address biological target structural diversity. It is thought that, based on Lipinski’s Rule of Five, up to 1060 druggable structures could be synthesised6. Just over 107 different drug structures, natural or synthetic, are reported in the Beilstein database of organic compounds, indicating that less than one trillionth of the total druggable chemical space is exploited to date7. For different reasons including costs, dwindling
pipelines and productivity issues, the pharmaceuti- cal industry needed to rethink its R&D strategies and the way drug discovery should be performed. A short-term tactic used by most major pharmaceuti- cal companies was to acquire new drug pipeline content through merger and acquisition activities. Longer-term, several companies opted to decen- tralise their research programmes via collaborative efforts with external partners. Several academic-
Drug Discovery World Fall 2018
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