Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Apr 17;4(4):245-7.
doi: 10.1021/cb9000712.

Hydrating for resistance to radicicol

Adam S Duerfeldt  1 , Brian S J Blagg
Affiliations
Review

Hydrating for resistance to radicicol

Adam S Duerfeldt et al. ACS Chem Biol. .

Abstract

Resistance to Hsp90 inhibition has become an important concern as several clinical trials are currently in progress for the treatment of cancer. A summary of known mechanisms of resistance to Hsp90 inhibitors is provided, including the recent solution of the Humicola fuscoatra Hsp90 structure, the organism responsible for the biosynthesis of radicicol. Through careful analyses of Hsp90 structures, a plausible mechanism for resistance to Hsp90 inhibitors has been obtained by single mutations about the N-terminal ATP-binding site.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Hsp90 N-terminal ligands.
Figure 2
Figure 2
Mechanisms of resistance to Hsp90 inhibitors: a) drug efflux via P-gp pumps; b) induction of heat shock response; c) decreased NQ01 enzymatic activity, which is responsible for reduction of the GDA quinone to the higher affinity hydroquinone; d) competitive binding of p23/Sba1 to the Hsp90 N-terminus; and e) mutation to the N-terminal binding pocket (L34I), which alters the hydration state.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

  • Hsp90 inhibition: elimination of shock and stress.
    Duerfeldt AS, Blagg BS. Duerfeldt AS, et al. Bioorg Med Chem Lett. 2010 Sep 1;20(17):4983-7. doi: 10.1016/j.bmcl.2010.06.108. Epub 2010 Jul 1. Bioorg Med Chem Lett. 2010. PMID: 20656483 Free PMC article.
  • Macrocyclic inhibitors of hsp90.
    Johnson VA, Singh EK, Nazarova LA, Alexander LD, McAlpine SR. Johnson VA, et al. Curr Top Med Chem. 2010;10(14):1380-402. doi: 10.2174/156802610792232088. Curr Top Med Chem. 2010. PMID: 20536417 Free PMC article. Review.

References

    1. Pearl LH, Prodromou C, Workman P. The Hsp90 molecular chaperone: an open and shut case for treatment. Biochem J. 2008;410:439–453. - PubMed
    1. Wanping X, Neckers L. Targeting the molecular chaperone heat shock protein 90 provides a multifaceted effect on diverse cell signaling pathways of cancer. Clin Cancer Res. 2007;13:1625–1629. - PubMed
    1. Prodromou C, Nuttall J, Millson S, Roe S, Pearl L, Workman P, Tiow-Suan S, Tan D, Piper P. The structural basis of the radicicol resistance displayed by a fungal Hsp90. ACS Chem Biol. 2009;4:289–297. - PubMed
    1. Benchekroun MN, Schneider E, Safa AR, Townsend AJ, Sinha BK. Mechanisms of resistance to ansamycin antibiotics in human breast cancer cells lines. Mol Pharmacol. 1994;46:677–684. - PubMed
    1. Madden TA, Pumford S, Barrow D, Dutkowski CM, McClelland R, Nicholson RI. Development of acquired resistance to 17(allylamino)-17-demethoxygeldanamycin (17-AAG) in hormone refractory breast cancers in vitro. Proc Am Assoc Cancer Res. 2005;46 Abstract LB-267.

MeSH terms