Synthesis and biological activities of novel 17-aminogeldanamycin derivatives

Tian, Zong-Qiang; Liu, Yaoquan; Zhang, Dan; Wang, Zhan; Dong, Steven D.; Carreras, Christopher W.; Zhou, Yiqing; Rastelli, Giulio; Santi, Daniel V.; Myles, David C.

doi:10.1016/j.bmc.2004.07.053

Cited by 147 publications

(120 citation statements)

References 32 publications

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“…In a more recent study, a conserved hydrophobic motif in HSP90 β strand has been reported to regulate the secretion and function of HSP90 (30). Thus, the presence of detergent can influence 17AAG binding to HSP90, potentially contributing to the poor correlation between binding affinity and cytotoxicity (31,32) or to the potency gap between biochemical binding and Her2 degradation (33). We tested detergent by itself and found that 17AAG can significantly bind to detergent micelles.…”

Section: Discussionmentioning

confidence: 94%

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

Xie

Wondergem

Shen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Geldanamycin and its derivative 17AAG [17-(Allylamino)-17-demethoxygeldanamycin, telatinib] bind selectively to the Hsp90 chaperone protein and inhibit its function. We discovered that these drugs associate with mitochondria, specifically to the mitochondrial membrane voltage-dependent anion channel (VDAC) via a hydrophobic interaction that is independent of HSP90. In vitro, 17AAG functions as a Ca 2+ mitochondrial regulator similar to benzoquinone-ubiquinones like Ub0. All of these compounds increase intracellular Ca 2+ and diminish the plasma membrane cationic current, inhibiting urokinase activity and cell invasion. In contrast, the HSP90 inhibitor radicicol, lacking a bezoquinone moiety, has no measurable effect on cationic current and is less effective in influencing intercellular Ca 2+ concentration. We conclude that some of the effects of 17-AAG and other ansamycins are due to their effects on VDAC and that this may play a role in their clinical activity.

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Section: Discussionmentioning

confidence: 94%

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

Xie

Wondergem

Shen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…For instance, heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of several oncoproteins, such as Src, c-Raf, Bcr-Abl, Flt3, Akt, and Her2. The geldanamycin analogues 17-allylamino-demethoxygeldanamycin (43) and 17-(2-dimethylaminoethyl)amino-17-demethoxy-geldanamycin (44) inhibit Hsp90, causing destabilization of Hsp90 client proteins, which leads to their degradation (43). Promising use of Hsp90-active agents was reported with imatinib against CML cell lines (45) and with the Flt3 inhibitor PKC412 in acute myelogenous leukemia lines expressing the mutant protein (46).…”

Section: Discussionmentioning

confidence: 99%

A Sequential Blockade Strategy for the Design of Combination Therapies to Overcome Oncogene Addiction in Chronic Myelogenous Leukemia

2006

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Some tumors are dependent on the continued activity of a single oncogene for maintenance of their malignant phenotype. The best-studied example is the Bcr-Abl fusion protein in chronic myelogenous leukemia (CML). Although the clinical success of the Abl kinase inhibitor imatinib against chronicphase CML emphasizes the importance of developing therapeutic strategies aimed at this target, resistance to imatinib poses a major problem for the ultimate success of CML therapy by this agent. We hypothesized a sequential blockade strategy that is designed to decrease the expression of the Bcr-Abl protein, with the goal of complementing the action of imatinib on kinase activity. In this study, flavopiridol, an inhibitor of transcription, homoharringtonine (HHT), a protein synthesis inhibitor, and imatinib were used singly and in combination against the Bcr-Abl-positive human CML cell line K562. Flavopiridol alone inhibited phosphorylation of the RNA polymerase II COOH-terminal domain, specifically reduced RNA polymerase II-directed mRNA synthesis, and decreased the Bcr-Abl transcript levels. HHT inhibited protein synthesis and reduced the Bcr-Abl protein level. Imatinib directly inhibited the kinase activity of Bcr-Abl. The combinations of flavopiridol and HHT and flavopiridol and imatinib synergistically decreased clonogenicity as evaluated by the median-effect method. Greater synergy was observed when HHT and imatinib were given sequentially compared with simultaneous administration. Imatinib-resistant Ba/F3 cells that were transfected to express the E255K and T315I mutations of Bcr-Abl were not cross-resistant to flavopiridol and HHT. These results provided a rationale for the combination of inhibitors of transcription and/or translation with specific kinase inhibitors. (Cancer Res 2006; 66(22): 10959-66)

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“…Included among these are 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin (17-DMAG, KOS1022; alvespimycin; compound 35, Figure 5; Tian et al, 2004;Hollingshead et al, 2005) and JPI-504 (compound 36, Figure 5; Ge et al, 2008), each having entered clinical trials.…”

Section: Phospholipids-antagonists Of Ph Domainsmentioning

confidence: 99%