Figure 8. Heterogeneity analysis applied throughout the early drug discovery process.

Heterogeneity analysis is required to guide decisions throughout the drug discovery process, beginning with defining disease relevant biology in clinical samples, and establishing benchmarks for subsequent analyses. Next disease relevant models, which by necessity will be heterogeneous, are developed and optimized. Heterogeneity is characterized in the models, and thresholds for HI's are established along with potency criteria to select hits. Screening hits are advanced to secondary assays based on their potency and HI profile. Heterogeneity of response to compounds will be model dependent, and assessing heterogeneity in orthogonal secondary assays will provide insights into understanding the MOA. Monitoring the heterogeneity profile during SAR and lead optimization is essential to keeping lead development on target and mechanism of the disease relevant biology.