US EPA

7436887 

Journal Article 

Novobiocin: redesigning a DNA gyrase inhibitor for selective inhibition of hsp90 

Burlison, JA; Neckers, L; Smith, AB; Maxwell, A; Blagg, BS 

2006 

Yes 

Journal of the American Chemical Society
ISSN: 0002-7863
EISSN: 1520-5126 

128 

48 

15529-15536 

English 

17132020 

10.1021/ja065793p 

WOS:000242367000037 

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. 

Binding energy; Degradation; DNA; Enzyme inhibition; Hydroxylation; Molecular structure; Coumermycin; Deshydroxy novobiocin (DHN1); Gyrase; Novobiocin; Antibiotics; 3' descarbamoyl 4 deshydroxynovobiocin; 4 deshydroxynovobiocin; adenosine triphosphate; antibiotic agent; carbamic acid; clorobiocin; coumamycin; coumamycin A1; coumarin; DNA topoisomerase (ATP hydrolysing); geldanamycin; gyrase inhibitor; heat shock protein 90; hydroxyl group; natural product; novobiocin; radicicol; article; carboxy terminal sequence; controlled study; drug binding site; drug classification; drug design; drug potency; drug protein binding; drug screening; drug selectivity; drug specificity; drug synthesis; enzyme inhibition; human; human cell; protein degradation; structure activity relation; Binding Sites; Blotting, Western; Cell Line, Tumor; Cell Survival; DNA Gyrase; HSP90 Heat-Shock Proteins; Humans; Molecular Structure; Novobiocin; Protein Folding; Structure-Activity Relationship; Substrate Specificity