Dihydroquinone ansamycins: toward resolving the conflict between low in vitro affinity and high cellular potency of geldanamycin derivatives.

Abstract

Heat shock protein 90 (Hsp90) is critical for the maturation of numerous client proteins, many of which are involved in cellular transformation and oncogenesis. The ansamycins, geldanamycin (GA) and its derivative, 17-allylaminogeldanamycin (17-AAG), inhibit Hsp90. As such, the prototypical Hsp90 inhibitor, 17-AAG, has advanced into clinical oncology trials. GA and 17-AAG potently inhibit tumor cell proliferation and survival but have been reported to bind weakly to Hsp90 in vitro. Recent studies have suggested that the in vitro potency of ansamycins against Hsp90 may be enhanced in the presence of cochaperones. Here, we present evidence of an alternative explanation. Ansamycins reduced to their dihydroquinones in the presence of common reducing agents in vitro have approximately 40-fold greater affinity than the corresponding oxidized quinones. The dihydroquinone of 17-AAG is not generated in an aqueous environment in the absence of reducing agents but is produced in both tumor and normal quiescent epithelial cells. The reduced form of 17-AAG is differentiated from its oxidized form not only by the higher affinity for Hsp90 but also by a protracted K(off) rate. Therefore, the in vivo accumulation of the high-affinity dihydroquinone ansamycins in tumor cells contributes to the antitumor activity of these compounds and alters our understanding of the active species driving the efficacy of this class of compounds.

• Authors: Anna C Maroney, Juan J Marugan, Tara M Mezzasalma, Alexander N Barnakov, Thomas A Garrabrant, Larry E Weaner, William J Jones, Ludmila A Barnakova, Holly K Koblish, Matthew J Todd, John A Masucci, Ingrid C Deckman, Robert A Galemmo Jr, Dana L Johnson
• Journal: Biochemistry (Biochemistry) Vol. 45 Issue 17 Pg. 5678-85 (May 02 2006) ISSN: 0006-2960 [Print] United States
• PMID: 16634649 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Quinones
• Reducing Agents
• Rifabutin
• tanespimycin
• geldanamycin

Topics

• Antineoplastic Agents
• Benzoquinones
• Cell Line, Tumor (drug effects)
• Cells, Cultured
• Drug Stability
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Lactams, Macrocyclic
• Protein Binding (drug effects)
• Quinones (metabolism, pharmacology)
• Reducing Agents (pharmacology)
• Rifabutin (analogs & derivatives, metabolism, pharmacology)
• Solubility