Convergent Synthesis and Discovery of a Natural Product-Inspired Paralog-Selective Hsp90 Inhibitor (original) (raw)
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Engineered Biosynthesis of Geldanamycin Analogs for Hsp90 Inhibition
Chemistry & Biology, 2004
dergo rapid degradation as a consequence of ubiquitination and subsequent catabolism by the proteosome. Zong-Qiang Tian, Greg O. Buchanan, The depletion of mature kinases results in a cytostatic Rika Regentin, Zhihao Hu, C.R. Hutchinson, effect or, in some cases, apoptosis and cell death. and Robert McDaniel* Thus, as a potential new target for cancer therapy, the Kosan Biosciences, Inc. discovery that Hsp90 and one or more of its protein 3832 Bay Center Place kinase cohorts are overproduced in several types of hu-Hayward, California 94545 man cancers has led to further interest in geldanamycin and its analogs [16, 17]. Many geldanamycin analogs have been produced by Summary replacement of the C-17 O-methoxy group with substituted amines [18, 19]. One such drug, 17-allylamino-17-Geldanamycin, a polyketide natural product, is of sigdemethoxygeldanamycin (17-AAG), is currently undernificant interest for development of new anticancer going phase I and II clinical trials [20]. Experience with drugs that target the protein chaperone Hsp90. While the behavior of geldanamycin and 17-AAG in animals the chemically reactive groups of geldanamycin have and humans has pointed to the need for more water been exploited to make a number of synthetic anasoluble and less hepatotoxic forms of this drug [21, 22].
Bioorganic & Medicinal Chemistry Letters, 2008
Hsp90 is an attractive chemotherapeutic target because it is essential to maturation of multiple oncogenes. We describe the conformational significance of EH21A1-A4, phenolic derivatives of geldanamycin isolated from Streptomyces sp. Their native free structures are similar to the active form of geldanamycin bound to Hsp90 protein. Their conformational character is a probable reason for their high-affinity binding. Lack of toxic benzoquinone in EH21A1-A4 also adds to their potential as lead compounds for anti-tumor drugs.
Mechanistic Studies on Hsp90 Inhibition by Ansamycin Derivatives
Journal of Molecular Biology, 2007
Heat shock protein 90 (Hsp90) is a molecular chaperone that is required for the maturation and activation of a number of client proteins, many of which are involved in cancer development. The ansamycin family of natural products and their derivatives, such as geldanamycin (GA), are well-known inhibitors of the essential ATPase activity of Hsp90. Despite structural studies on the complexes of ansamycin derivatives with the ATPase domain of Hsp90, certain aspects of their inhibitory mechanism remain unresolved. For example, it is known that GA in solution exists in an extended conformation with a trans amide bond; however, it binds to Hsp90 in a significantly more compact conformation with a cis amide bond. GA and its derivatives have been shown to bind to Hsp90 with low micromolar affinity in vitro, in contrast to the low nanomolar anti-proliferative activity that these drugs exhibit in vivo. In addition, they show selectivity towards tumour cells. We have studied both the equilibrium binding, and the association and dissociation kinetics of GA derivative, 17-DMAG, and the fluorescently labelled analogue BDGA to both wild-type and mutant Hsp90. The mutants were made in order to test the hypothesis that conserved residues near the ATP-binding site may catalyse the trans-cis isomerisation of GA. Our results show that Hsp90 does not catalyse the trans-cis isomerisation of GA, and suggests that there is no isomerisation step before binding to Hsp90. Experiments with BDGA measured over a wide range of conditions, in the absence and in the presence of reducing agents, confirm recent studies that have suggested that the reduced dihydroquinone form of the drug binds to Hsp90 considerably more tightly than the non-reduced quinone species.
Synthesis and evaluation of Hsp90 inhibitors that contain the 1,4-naphthoquinone scaffold
Bioorganic & Medicinal Chemistry, 2009
High-throughput screening of a library of diverse molecules has identified the 1,4-naphthoquinone scaffold as a new class of Hsp90 inhibitors. The synthesis and evaluation of a rationally-designed series of analogues containing the naphthoquinone core scaffold has provided key structure-activity relationships for these compounds. The most active inhibitors exhibited potent in vitro activity with low micromolar IC 50 values in anti-proliferation and Her2 degradation assays. In addition, 3g, 12, and 13a induced the degradation of oncogenic Hsp90 client proteins, a hallmark of Hsp90 inhibition. The identification of these naphthoquinones as Hsp90 inhibitors provides a new scaffold upon which improved Hsp90 inhibitors can be developed.
Cancer chemotherapy and pharmacology, 1998
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.
Design of novel Geldanamycin analogue hsp90 alpha-inhibitor in silico for breast cancer therapy
Medical Hypotheses, 2013
Background: Geldanamycin, which is one of the most potent and effective hsp90 alpha inhibitor until date, is normally used to target breast cancer. Inhibition of hsp90 alpha leads to the degradation of client proteins involved in the initiation and progress of breast cancer pathogenesis. Hence, Geldanamycin has been widely pursued as a treatment option for breast cancer. However, it failed to move into the clinics due to the toxicity associated with its solubility. Geldanamycin was modified chemically to develop 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) and later 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), which have higher solubility and lesser toxicity. Nonetheless, in order to achieve highest efficacy against breast cancer, a more potent, soluble and least toxic hsp90 alpha inhibitors need to be developed. Hypothesis: We hypothesize that designing a novel Geldanamycin analogue with increased affinity and efficacy would provide a probability of having less toxic effect in the therapy of breast cancer. We also hypothesize that hsp90 alpha forms a multi-chaperone complex with hsp70 and hsp40 and thus assist the folding and maturation of number of client proteins including cellular p53. We further hypothesize that the higher binding affinity of the novel Geldanamycin analogue for hsp90 alpha triggers the degradation of nonfunctional mutant p53 by cellular proteasomes. Experimental design: Ten different Geldanamycin analogues were designed using Marvinsketch software. Binding affinity of hsp90 alpha and its complex (hsp70, hsp40) with wild type p53 and mutant p53 were determined using Hex 6.3. Binding affinities of ten different analogues for hsp90 alpha were determined by estimating binding energies of molecules using Hex 6.3 and Autodock 4.0 softwares. Results: The estimation of molecular docking energies using Hex 6.3 and Autodock 4.0 software proved that Analogue 9 was the best hsp90 alpha inhibitor among all ten analogues designed and the existing inhibitors. Following hsp90 alpha inhibition using Analogue 9 and subsequent docking results using Hex 6.3 software showed less binding affinity of Analogue 9 for mutant p53 than the wild version, suggesting the increased chance of the degradation of mutant p53 by cellular machines. Conclusions: Based on our findings, we propose Analogue 9 to be the more efficient hsp90 alpha inhibitor than existing inhibitors. Furthermore, the chemical synthesis of Analogue 9 at the laboratory scale and successful in vitro and in vivo studies in breast cancer model would lead the compound into the clinical stage.
Proceedings of the National Academy of Sciences of the United States of America, 2006
Heat shock protein (Hsp)90 is emerging as an important therapeutic target for the treatment of cancer. Two analogues of the Hsp90 inhibitor geldanamycin are currently in clinical trials. Geldanamycin (GA) and its analogues have been reported to bind purified Hsp90 with low micromolar potency, in stark contrast to their low nanomolar antiproliferative activity in cell culture and their potent antitumor activity in animal models. Several models have been proposed to account for the approximately 100-fold-greater potency in cell culture, including that GA analogues bind with greater affinity to a five-protein Hsp90 complex than to Hsp90 alone. We have determined that GA and the fluorescent analogue BODIPY-GA (BDGA) both demonstrate slow, tight binding to purified Hsp90. BDGA, used to characterize the kinetics of ligand-Hsp90 interactions, was found to bind Hsp90alpha with k(off) = 2.5 x 10(-3) min(-1), t(1/2) = 4.6 h, and Ki* = 10 nM. It was found that BDGA binds to a functional multip...