1. Academic Validation
  2. Synthesis and biological activities of novel 17-aminogeldanamycin derivatives

Synthesis and biological activities of novel 17-aminogeldanamycin derivatives

  • Bioorg Med Chem. 2004 Oct 15;12(20):5317-29. doi: 10.1016/j.bmc.2004.07.053.
Zong-Qiang Tian 1 Yaoquan Liu Dan Zhang Zhan Wang Steven D Dong Christopher W Carreras Yiqing Zhou Giulio Rastelli Daniel V Santi David C Myles
Affiliations

Affiliation

  • 1 Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, CA 94545, USA. [email protected]
Abstract

Geldanamycin interferes with the action of heat shock protein 90 (HSP90) by binding to the N-terminal ATP binding site and inhibiting an essential ATPase activity. In a program directed toward finding potent, water soluble inhibitors of HSP90, we prepared a library of over sixty 17-alkylamino-17-demethoxygeldanamycin analogs, and compared their affinity for HSP90, ability to inhibit growth of SKBr3 mammalian cells, and in selected cases, water solubility. Over 20 analogs showed cell growth inhibition potencies similar to that of 17-allylamino-17-demethoxygeldanamycin (17-AAG), the front-runner geldanamycin analog that is currently in multiple clinical trials. Many of these analogs showed water solubility properties that were desirable for formulation. One of the most potent and water-soluble analogs in the series was 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin (17-DMAG), which was independently prepared by the NCI and will soon enter clinical trials. Importantly, the binding affinity of these analogs to the molecular target HSP90 does not correlate well with their cytotoxicity in SKBr3 cells.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-136312
    HSP90 Inhibitor
    HSP