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An analysis of over a thousand experimental drug candidates that found molecules with few rotatable bonds and a modest polar surface area were far more likely to be absorbed when swallowed, giving medicinal chemists two simple rules that shaped the design of oral cancer drugs.
Veber and colleagues at GlaxoSmithKline analysed rat oral bioavailability data for about 1,100 drug candidates and related it to calculated molecular properties. Compounds with ten or fewer rotatable bonds and a polar surface area of 140 square angstroms or less (or twelve or fewer hydrogen bond donors and acceptors) had a high probability of good oral bioavailability, largely independent of molecular weight, which had been the emphasis of earlier rules. The paper argued that reduced molecular flexibility and polar surface area, not size alone, are what predict oral absorption.
Veber's rules, alongside Lipinski's rule of five, are used across the industry to decide whether a molecule can become a pill. They set the boundaries within which most oral kinase inhibitors and other targeted cancer drugs were designed, and the current push into larger molecules such as PROTACs and macrocycles is partly an effort to work beyond them.