Mitigating risk in academic preclinical drug discovery

Abstract

The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology.

Figure 1. Staying on the right track in academic drug discovery

The figure is based on a railway analogy of translational research as a track, with milestones shown as blue ovals. Although there are several favourable end points in academic drug discovery (for example, early licensing, Phase I studies and rapid no-go decisions; shown as green circles), there are just as many — if not more — opportunities for projects to become derailed or reach a dead end (shown in pink). Practicing sound strategies related to project organization, targets, assays, medicinal chemistry and preclinical pharmacology can help mitigate the risks of unfavourable outcomes. ADMET, absorption, distribution, metabolism, excretion and toxicology; HTS, high-throughput screening; SAR, structure–activity relationship.

Figure 2. Linking academic researchers with translational resources

An organized drug discovery institute and other specialty centres, together with the academic institute, can help enable a project to meet translational end points. Curiosity-driven researchers collaborating within the academic institute may have translatable projects. Centres within the university can help with the specialized research required for translation and act as intermediaries with contract research organizations for specialized assays and studies, collaborative groups, and funding agencies outside the institution. Academic researchers can also establish collaborative partnerships directly. ADMET, absorption, distribution, metabolism, excretion and toxicology; API, active pharmaceutical ingredient; HTS, high-throughput screening.

Figure 3. Assembling the experts

A large university can have much of the expertise necessary to assist in the translation of basic research into Phase I studies. Shown above is an outline of how this expertise is brought to bear on translational projects at the University of Minnesota, USA. ADME, absorption, distribution, metabolism, excretion; API, active pharmaceutical ingredient; GMP, good manufacturing practice; HTS, high-throughput screening; PD, pharmacodynamic; PK, pharmacokinetic. Adapted with permission from the University of Minnesota Therapeutics Development, Preclinical Testing and Clinical Trial Services brochure, University of Minnesota.

Figure 4. p-hydroxyarylsulfonamides as examples of nuisance compounds

There have been several reports in reputable journals of compounds bearing the p-hydroxyarylsulfonamide chemotype as being active in unrelated bioasssays^–, despite either being flagged as pan-assay interference compounds (PAINS) or closely resembling the ‘sulfonamide_B’ PAINS substructure shown in the figure. The bioassay promiscuity of p-hydroxyarylsulfonamides probably stems from a combination of compound instability, thiol-reactivity and redox activity. BRAF^V600E, B-rapidly accelerated fibrosarcoma V600E; CT-L, chymotrypsin-like; KEAP1, kelch-like ECH-associated protein; MCL1, myeloid cell leukaemia 1; NRF2, NFE2-related factor 2.

Figure 5. Interconnected stages and cycles in lead discovery project development

Drug discovery projects typically involve a target or phenotype identification, characterization and validation phase. This is usually followed by the design, optimization and validation of high-throughput screening (HTS) or related assays aimed at lead discovery, along with development of orthogonal assays and key counter-screens. Chemotypes for further investigation should be selected to have the desired physicochemical and experimental parameters relevant to project success. The top chemical entities with confirmed bioactivity and other desirable traits relevant for the project (for example, selectivity and lead-like properties) should then be investigated in higher-order experiments (preclinical pharmacology) such as cell-based assays and mechanism-of-action (MOA) explorations. The dotted arrow represents drug repurposing. HCS, high-content screening. Adapted with permission from REF., Elsevier.

Figure 6. Examples of less obvious problematic compounds

Rhodanines (such as 1), polyhydroxylated phytochemicals such as as epigallocatechin gallate (2), tetra hydro-3H-cyclopenta[c]quinolines (such as 3) and 2-acetamidothiophene-3-carboxylates (such as 4) are identified as hits in many high-throughput screening campaigns but are most likely false positives. Cell membrane perturbations have recently been shown to be a potential source of assay interference by compounds such as epigallocatechin gallate (2).

Figure 7. Examples of suspicious and useful structure–activity relationships

Structure–activity relationships (SARs; half-maximal inhibitory concentrations) reported for two chemical series developed for two different targets: aldose reductase (part a) and CDK2 (REF. 102) (part b). The compounds in part a show a flat SAR in which both minor (highlighted in pink) and major (highlighted in blue) changes to the molecular structure lead to insignificant changes in activity, whereas the compounds in part b show a profound increase in potency as rational changes (highlighted in pink) are made within the series. A threefold to tenfold difference in the potency of well-designed analogues at <25 μM activity typically bodes well for series optimization.