Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus.
Inhibition of the protein chaperone Hsp90 is a promising new approach to cancer therapy. We describe the preparation of potent non-benzoquinone ansamycins. One of these analogues, generated by feeding 3-amino-5-chlorobenzoic acid to a genetically engineered strain of Streptomyces hygroscopicus, shows high accumulation and long residence time in tumor tissue, is well-tolerated upon intravenous dosing, and is highly efficacious in the COLO205 mouse tumor xenograft model.
Menzella
Hugo G
HG
Kosan Biosciences Incorporated, 3832 Bay Center Place, Hayward, California 94545, USA. menzella@ibr.gov.ar
Tran
Thomas-Toan
TT
Carney
John R
JR
Lau-Wee
Janice
J
Galazzo
Jorge
J
Reeves
Christopher D
CD
Carreras
Christopher
C
Mukadam
Sophie
S
Eng
Sara
S
Zhong
Ziyang
Z
Timmermans
Pieter B M W M
PB
Murli
Sumati
S
Ashley
Gary W
GW
D002151:Calorimetry; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D005818:Genetic Engineering; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D017828:Rifabutin / Q000494:pharmacology*; D013302:Streptomyces / Q000235:genetics*
D018841:HSP90 Heat-Shock Proteins; D017828:Rifabutin