Lead Optimization in Drug Discovery

Abstract Lead optimization in drug discovery has changed significantly over the past five years and no longer is fragmented into separate hit‐to‐lead and lead optimization phases. Chemical lead optimization from high‐throughput screening (HTS) to clinical candidate identification is now one seamless process that draws on new technologies for accelerated synthesis, purification, and screening of directed, iterative compound libraries. Advances In high‐throughput screening technologies allow detection of new allosteric modes of target modulation, which provides new chemotypes and target opportunities. With the incorporation of drug metabolism and pharmacokinetics (DMPK) inputs early in the lead optimization work flow, molecules are not optimized solely for target potency and selectivity. Moreover, “closed‐loop” work flows are in place such that synthesis and primary screening operate on a 1‐week turnaround for up to 48 compounds/week with DMPK data cycling every other week to guide compound design, which provides expedited timelines for the development of proof‐of‐concept compounds and clinical candidates with limited human resources.