Rational hopping of a peptidic scaffold into non-peptidic scaffolds: structurally novel potent proteasome inhibitors derived from a natural product, belactosin A.

Rational scaffold hopping of a natural product belactosin A derivative was successfully achieved based on the pharmacophore model constructed. The peptidic scaffold was replaced by significantly simplified non-peptidic scaffolds, by which weak belactosin A (IC50 = 1440 nM) was converted into highly potent non-peptidic inhibitors (IC50 = 26-393 nM).