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).
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. shu@pharm.hokudai.ac.jp.
Shuhei
S
Kawamura
Yuka
Y
Unno
Takatsugu
T
Hirokawa
Akira
A
Asai
Mitsuhiro
M
Arisawa
Satoshi
S
Shuto
D001688:Biological Products / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides / Q000737:chemistry*; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology
D001688:Biological Products; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D061988:Proteasome Inhibitors; C406052:belactosin A