tanespimycin and geldanamycin

The discovery and clinical development of heat shock protein 90 (Hsp90) inhibitors continue to progress. A number of Hsp90 inhibitors are in clinical trials, and preclinical discoveries of new chemotypes that bind to distinct regions in the protein as well as isoform selective compounds are active areas of research. This review will highlight progress in the field since 2010.

Topics: Animals; Antineoplastic Agents; Benzoquinones; Drug Design; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Neoplasms; Neuroprotective Agents; Protein Isoforms; Rats; tau Proteins

The nucleophilic attack of amines at C(17) or C(17)/C(20) positions of geldanamycin's (GDM) benzoquinone, via initial 1,4-Michael conjugate addition mechanism, yield new analogs with closed or open ansa-bridges (1-31), respectively. X-ray structures of analogs 22 and 24 reveals an unexpected arrangement of the ansa-bridge in solid (conformer B), that is located between those of conformers A, prevailing in solution (trans-lactam), and C, crucial at binding to Hsp90 (cis-lactam). The structure of a new-type conformer B allows to better understand the molecular recognition mechanism between the GDM analogs and the target Hsp90. Combined analysis of: anticancer test results (SKBR-3, SKOV-3, PC-3, U-87, A-549) and those performed in normal cells (HDF), K

Topics: Amines; Antineoplastic Agents; Benzoquinones; Cell Proliferation; Cells, Cultured; Density Functional Theory; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Lactams, Macrocyclic; Molecular Structure; Structure-Activity Relationship

Twenty-six 17-phenylethylamine-modified geldanamycin derivatives were synthesized and evaluated for antiproliferation activity in human cancer cell lines, LNCaP and MDA-MB-231. Five derivatives (2j, 2q, 2v, 2x, and 2 y) showed excellent in vitro antitumor activities. Among them, compound 2 y was the most potent lead, with IC50 values of 0.27 ± 0.11 and 0.86 ± 0.23 μm for LNCaP and MDA-MB-231, respectively. In particular, compound 2 y was more active than its precursor geldanamycin against LNCap cells. Liver injury test in mice demonstrated that 2 y group showed no significant difference for serum alanine aminotransferase (ALT) activity versus vehicle control, indicating that 2 y was a promising antitumor candidate. Preliminary structure-activity relationship (SAR) and molecular dynamics (MD) simulations of this new series of geldanamycin derivatives were also investigated, suggesting a theoretical model of 17-phenylethylaminegeldanamycins binding to Hsp90.

Topics: Animals; Antineoplastic Agents; Benzoquinones; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Male; Mice; Neoplasms; Structure-Activity Relationship

The high sequence conservation of druggable pockets of closely related proteins can make it challenging to develop selective inhibitors. We designed a new drug discovery approach that exploits both the static and dynamic differences of two orthologues. We applied it, as a proof of concept, to identify compounds that discriminate between the molecular chaperone Hsp90 of the protozoan pathogen Plasmodium falciparum (Pf) and that of its human host. We found that the ATP-binding pocket has a Pf-specific extension, whose sequence lining is identical in human Hsp90 but which differs by tertiary structure and dynamics. Using these insights for a structure-based drug screen, we discovered novel 7-azaindole compounds that exclusively bind the recombinant N-terminal domain of PfHsp90 but not of human Hsp90 nor of a PfHsp90 mutant with "human-like" dynamics. Moreover, these compounds preferentially inhibit the growth of yeast complemented by PfHsp90 and block the growth of Pf in culture.

Topics: Adenosine Triphosphate; Amino Acid Sequence; Animals; Antimalarials; Benzoquinones; Cell Survival; Computational Biology; Cysteine Proteinase Inhibitors; Drug Discovery; High-Throughput Screening Assays; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Models, Molecular; Molecular Sequence Data; Plasmids; Plasmodium falciparum; Protein Conformation; Rats; Saccharomyces cerevisiae; Structure-Activity Relationship

Thirty-three 17-arylmethylamine-substituted derivatives of geldanamycin (GA) were designed, synthesized and evaluated for the anti-proliferation activity on human cancer cell lines, LNCaP and MDA-MB-231. Three derivatives (22, 33 and 34) exhibited potent cytotoxicity with IC50 values range from 0.05 to 0.51 μM against both cell lines. Hepatotoxicity test in mice demonstrated that the levels of both AST and ALT of 34-treated group were lower than that of 17-AAG group. Western blot assay indicated that 34 was more potent than 17-AAG in the down-regulation of Hsp90 client proteins CDK4, Her2, EGFR and Raf. Moreover, 34 showed excellent in vivo antitumor activity in the MDA-MB-231 xenograft nude mice, which is superior to 22 and 33, and 17-AAG, indicating that 34 was a promising antitumor candidate. Additionally, preliminary structure-activity relationship (SAR) and molecular dynamics (MD) simulations of this new series of GA derivatives were also investigated, suggesting a theoretical model of 17-arylmethylamine geldanamycins binding to Hsp90.

Topics: Animals; Antineoplastic Agents; Benzoquinones; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; Drug Design; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Liver; Male; Mice; Models, Molecular; Protein Conformation

Heat shock protein 90 (Hsp90) is an attractive target for the development of antitumor agents. Geldanamycin (GA), the first Hsp90 inhibitor, has potent antitumor activity, but showed significant hepatotoxicity. To get rid of the hepatotoxicity of GA, in this study we incorporated aroyl groups via three types of linkers (4-aminomethylpiperidine, 1,4-butanediamine, and 1,6-hexanediamine) to the 17-position of GA and synthesized fifty-three 17-diamine-linked 17-aroylamido-17-demethoxygeldanamycins. All the derivatives were evaluated by MTT assay for their inhibitory activities against human breast cancer cell line MDA-MB-231. Among these compounds, 17-(6-(3,4,5-trimethoxycinnamamido)hexylamino)-17-demethoxygeldanamycin (7h29) showed the most potent cytotoxicity against MDA-MB-231 (IC50 = 0.19 ± 0.02 μM) with the lowest hepatotoxicity (AST = 181.0 ± 23.6 U/L, ALT = 40.4 ± 11.8 U/L). Compared to tanespimycin (17-AAG), 7h29 exhibited lower hepatotoxicity in mice, higher Hsp90 inhibitory activity in vitro and antitumor activity in human breast carcinoma (MDA-MB-231) xenograft nude mice.

Topics: Animals; Antineoplastic Agents; Benzoquinones; Cell Line, Tumor; Diamines; Female; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Mice; Molecular Docking Simulation; Protein Conformation; Xenograft Model Antitumor Assays

17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the activity of Hsp90, an important target for treatment of cancers. In an effort to identify analogues of geldanamycin (GDM) with properties superior to those of 17-AAG, we synthesized C-11 modified derivatives of GDM including ethers, esters, carbazates, ketones, and oximes and measured their affinity for Hsp90 and their ability to inhibit growth of human cancer cells. In accordance with crystal structures reported for complexes of GDMs with Hsp90, bulky groups attached to C-11 interfered with Hsp90 binding while smaller groups such as 11-O-methyl allowed Hsp90 binding. In addition, these analogues also showed in vitro cytotoxicity against human cancer cell lines. Esterification of the 11-OH of 17-AAG eliminated Hsp90 binding in vitro. The readily hydrolyzed esters acted as prodrugs during the measurement of cytotoxicity. Thus, during these experiments, the esters were hydrolyzed, releasing 17-AAG. Several 11-O-methyl-17-alkylaminogeldanamycin analogues were identified with improved potency relative to 17-AAG.

Topics: Antineoplastic Agents; Benzoquinones; Cell Line, Tumor; Cell Proliferation; Esters; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Prodrugs; Protein Binding; Structure-Activity Relationship

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.

Topics: Antineoplastic Agents; Benzoquinones; Cell Line, Tumor; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Models, Molecular; Molecular Structure; Streptomyces

Geldanamycin (1), an antifungal and anticancer ansamycin, was reported as a neurotrophic and neuroprotective substance against antineoplastic drugs, paclitaxel, vincristine, and cisplatin, on cultured dorsal root ganglion neurons from chick embryos. In this study, 1 in a large quantity, together with a known 17-O-demethylgeldanamycin (2), and a new 17-O-demethylgeldanamycin hydroquinone (3) were obtained from a mangrove Streptomyces sp. A series of O-alkyl and N-alkyl derivatives of 1 were prepared by modification of C-17 and/or C-19 on the quinone ring and were evaluated for in vitro activity against P19-derived neurons. Compound 1 and 19-O-methylgeldanamycin (7) at a very low dose (1nM) enhanced survival and neurite outgrowth of P19-derived neurons and prevented neurotoxicity of paclitaxel and vinblastine. Compound 7, possessing the lowest cytotoxicity and neurotoxicity, is serving as the most promising candidate in neurodegenerative therapy against neurotoxic anticancer drugs.

Topics: Animals; Benzoquinones; Cells, Cultured; Chick Embryo; Ganglia, Spinal; Lactams, Macrocyclic; Molecular Structure; Neurons; Neuroprotective Agents; Structure-Activity Relationship

The synthesis and evaluation of several chemical modulators of heat shock protein 90 (Hsp90) dimerization is presented. These agents may represent useful tools to study the importance of N-terminal dimerization and also to determine subunit interface(s) in Hsp90.

Topics: Benzoquinones; Binding, Competitive; Dimerization; HSP90 Heat-Shock Proteins; Lactams, Macrocyclic; Molecular Structure; Quinones; Stereoisomerism; Structure-Activity Relationship

The synthesis of a red-shifted cy3B-GM ligand and its evaluation as a fluorescence polarization probe for Hsp90 is presented.

Topics: Benzoquinones; Carbocyanines; Color; Fluorescence Polarization; Fluorescent Dyes; HSP90 Heat-Shock Proteins; Lactams, Macrocyclic; Ligands; Molecular Structure; Rifabutin

Two new geldanamycin derivatives produced by genetic engineering of Streptomyces hygroscopicus strain K309-27-1 were isolated and characterized. Removal of the 8-methyl group of geldanamycin was achieved by replacing the AT4 domain of the polyketide synthase with a malonyl AT domain. The resulting strain produced 8-demethyl geldanamycin (2) and 4,5-epoxy-8-demethylgeldanamycin (3). The structures of both molecules were elucidated through interpretation of 1D and 2D NMR data as well as comparison with authentic geldanamycin derivatives. Compounds 2 and 3 displayed moderate cytotoxicity against the human breast cancer cell line SK-BR-3.

Topics: Antibiotics, Antineoplastic; Benzoquinones; Cell Line, Tumor; Genetic Engineering; Humans; Lactams, Macrocyclic; Molecular Structure; Quinones; Streptomyces; Structure-Activity Relationship

Several LY294002-GM heterodimers were synthesized with the intent of modulating their activity in the presence of hsp90 and thereby creating selective inhibitors of PI3K and PI3K-related family.

Topics: Ataxia Telangiectasia Mutated Proteins; Benzoquinones; Cell Cycle Proteins; Chromones; Dimerization; DNA-Activated Protein Kinase; DNA-Binding Proteins; HSP90 Heat-Shock Proteins; Inhibitory Concentration 50; Lactams, Macrocyclic; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Protein Serine-Threonine Kinases; Quinones; Tumor Suppressor Proteins

The erbB-2 oncogene encodes a transmembrane protein tyrosine kinase which plays a pivotal role in signal transduction and has been implicated when overexpressed in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the quinoid moiety of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2 (FRE/erbB-2). Specifically, dosed intraperitoneally at 100 mg/kg, 17-(allylamino)-17-demethoxygeldanamycin and other 17-amino analogs were effective at reducing p185 phosphotyrosine in subcutaneous flank FRE/erbB-2 tumors. Modifications to the 17-19-positions of the quinone ring revealed a broad structure-activity relationship in vitro.

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Benzoquinones; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Lactams, Macrocyclic; Mice; Mice, Nude; Phosphotyrosine; Protein-Tyrosine Kinases; Quinones; Rats; Receptor, ErbB-2; Rifabutin; Structure-Activity Relationship; Transfection; Tumor Cells, Cultured

Overexpression of the erbB-2 oncogene has been linked to poor prognosis in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the ansa ring of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2. Functional group modification in the ansa ring was performed stereoselectively and regiospecifically without the need for protection strategies. Essential functional groups that were required for anti-erbB-2 activity were the 7-carbamate and the 2,3-double bond. Modification of the functional groups at the other positions was permitted. Structure-activity relationships are described for 1-5-, 7-9-, 11-, 15-, and 22-substituted geldanamycins.

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Benzoquinones; Breast Neoplasms; Female; Genes, erbB-2; Humans; Lactams, Macrocyclic; Mice; Mice, Nude; Molecular Conformation; Molecular Structure; Protein-Tyrosine Kinases; Quinones; Rats; Receptor, ErbB-2; Structure-Activity Relationship; Transfection