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Small Molecule Discovery Center
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Hit-to-Lead Chemistry

The chemical optimization process begins with one or more validated hits from a high-throughput assay. Hit validation is an essential first step before chemistry resources can be allocated to an optimization effort. Validation studies involve confirmation of the chemical structures and biological activity of hits identified in the primary screen. The SMDC provides limited analytical support for structure confirmation but secondary biological assays (e.g. dose-response studies) are typically conducted in the user's lab with hits cherry-picked by the SMDC. After validation, SMDC chemists evaluate the suitability of the project for subsequent chemical optimization studies. The SMDC makes the final determinations as to which hits/targets are pursued in a hit-to-lead chemistry effort. We expect that around one quarter of screening projects will lead to chemical optimization studies.

The goal of the hit-to-lead chemistry process is to identify new analogs with improved potency, reduced off-target activities, and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics. This optimization is accomplished through empirical modification of the hit structure and/or by employing structure-based design if structural information about the target is available. We will often examine new chemical scaffolds that retain the molecular recognition features of the original hit but are more drug-like in nature (e.g., constrained systems, peptido-mimetics, etc.). Regardless of the approach, the process is iterative, with biological and/or structural data guiding the next round of inhibitor design. Thus, investigator labs are expected to carry out timely biochemical and/or cell-based evaluation of new analogs prepared by SMDC chemists. In vitro counter-assays that address cytotoxicity, permeability, and metabolic stability are usually performed in the SMDC. These counter-assays are designed to ensure that significant time and effort is not wasted on chemotypes with intrinsic liabilities. Hit-to-lead projects at the SMDC typically involve one or two medicinal chemists and can last anywhere from a few months to over a year.