What are hits, leads and clinical candidates?

Drug discovery projects use three words to describe how far a compound has come: hit, lead and candidate. Each step raises the bar for evidence.

Hit

A hit is a compound that shows activity against the target in a primary screen, often with modest potency (for example, an IC₅₀ in the micromolar range). Screens produce many false positives: compounds that aggregate, react with the assay, fluoresce or are simply impure. A hit is therefore only a starting point until it is re-tested from fresh material and shows a dose–response curve.

Lead

A lead is a confirmed hit that belongs to a series chemists can improve. Typical expectations are:

• reproducible activity with a clear structure–activity relationship (SAR) — small changes to the molecule change potency in understandable ways;
• reasonable selectivity against related proteins;
• acceptable early ADMET properties such as solubility and metabolic stability;
• room to make analogues: synthetic routes and available building blocks.

Moving from hits to leads is called hit-to-lead. Searching for close analogues of a hit, by similarity or substructure, is one of the fastest ways to build early SAR without new synthesis.

Clinical candidate

After lead optimization, the team nominates a single compound (often with a backup) for preclinical development. A candidate must be potent in disease models, have a pharmacokinetic profile that supports the intended dose, an acceptable safety margin, and a route to manufacture at scale.

Useful metrics along the way