Novobiocin: redesigning a DNA gyrase inhibitor for selective inhibition of hsp90.
Novobiocin is a member of the coumermycin family of antibiotics and is a well-established inhibitor of DNA gyrase. Recent studies have shown that novobiocin binds to a previously unrecognized ATP-binding site at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at approximately 700 microM. In an effort to develop more efficacious inhibitors of the C-terminal binding site, a library of novobiocin analogues was prepared and initial structure-activity relationships revealed. These data suggested that the 4-hydroxy moiety of the coumarin ring and the 3'-carbamate of the noviose appendage were detrimental to Hsp90 inhibitory activity. In an effort to confirm these findings, 4-deshydroxy novobiocin (DHN1) and 3'-descarbamoyl-4-deshydroxynovobiocin (DHN2) were prepared and evaluated against Hsp90. Both compounds were significantly more potent than the natural product, and DHN2 proved to be more active than DHN1. In an effort to determine whether these moieties are important for DNA gyrase inhibition, these compounds were tested for their ability to inhibit DNA gyrase and found to exhibit significant reduction in gyrase activity. Thus, we have established the first set of compounds that clearly differentiate between the C-terminus of Hsp90 and DNA gyrase, converted a well-established gyrase inhibitor into a selective Hsp90 inhibitor, and confirmed essential structure-activity relationships for the coumermycin family of antibiotics.
Burlison
Joseph A
JA
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott Hall 4070, Lawrence, Kansas 66045-7563, USA.
Neckers
Len
L
Smith
Andrew B
AB
Maxwell
Anthony
A
Blagg
Brian S J
BS
D001665:Binding Sites; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D009675:Novobiocin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D017510:Protein Folding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D059005:Topoisomerase II Inhibitors
D018841:HSP90 Heat-Shock Proteins; D059005:Topoisomerase II Inhibitors; D009675:Novobiocin