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1.  Synthesis and Biological Evaluation of Coumarin Replacements of Novobiocin as Hsp90 Inhibitors 
Bioorganic & medicinal chemistry  2014;22(4):1441-1449.
Since Hsp90 modulates all six hallmarks of cancer simultaneously, it has become an attractive target for the development of cancer chemotherapeutics. In an effort to develop more efficacious compounds for Hsp90 inhibition, novobiocin analogues were prepared by replacing the central coumarin core with naphthalene, quinolinone, and quinoline surrogates. These modifications allowed for modification of the 2-position, which was previously unexplored. Biological evaluation of these compounds suggests a hydrophobic pocket about the 2-position of novobiocin. Anti-proliferative activities of these analogues against multiple cancer cell lines identified 2-alkoxyquinoline derivatives to exhibit improved activity.
doi:10.1016/j.bmc.2013.12.056
PMCID: PMC3963410  PMID: 24461493
2.  Cruentaren A Binds F1F0 ATP Synthase To Modulate the Hsp90 Protein Folding Machinery 
ACS Chemical Biology  2014;9(4):976-985.
The molecular chaperone Hsp90 requires the assistance of immunophilins, co-chaperones, and partner proteins for the conformational maturation of client proteins. Hsp90 inhibition represents a promising anticancer strategy due to the dependence of numerous oncogenic signaling pathways upon Hsp90 function. Historically, small molecules have been designed to inhibit ATPase activity at the Hsp90 N-terminus; however, these molecules also induce the pro-survival heat shock response (HSR). Therefore, inhibitors that exhibit alternative mechanisms of action that do not elicit the HSR are actively sought. Small molecules that disrupt Hsp90-co-chaperone interactions can destabilize the Hsp90 complex without induction of the HSR, which leads to inhibition of cell proliferation. In this article, selective inhibition of F1F0 ATP synthase by cruentaren A was shown to disrupt the Hsp90-F1F0 ATP synthase interaction and result in client protein degradation without induction of the HSR.
doi:10.1021/cb400906e
PMCID: PMC4090037  PMID: 24450340
3.  Identification of a New Scaffold for Hsp90 C-Terminal Inhibition 
Inhibition of Hsp90 C-terminal function is an advantageous therapeutic paradigm for the treatment of cancer. Currently, the majority of Hsp90 C-terminal inhibitors are derived from novobiocin, a natural product traditionally used as an antibiotic. Assisted by molecular docking studies, a scaffold containing a biphenyl moiety in lieu of the coumarin ring system found in novobiocin was identified for development of new Hsp90 C-terminal inhibitors. Initial structure–activity studies led to derivatives that manifest good antiproliferative activity against two breast cancer cell lines through Hsp90 inhibition. This platform serves as a scaffold upon which new Hsp90 C-terminal inhibitors can be readily assembled for further investigation.
doi:10.1021/ml400404s
PMCID: PMC4027776  PMID: 24900777
Heat shock protein 90; Hsp90 C-terminal inhibitors; novobiocin; biphenyl; breast cancer
4.  Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities 
The interaction that occurs between molecules is a dynamic process that impacts both structural and conformational properties of the ligand and the ligand binding site. Herein, we investigate the dynamic cross-talk between a protein and the ligand as a source for new opportunities in ligand design. Analysis of the formation/disappearance of protein pockets produced in response to a first-generation inhibitor assisted in the identification of functional groups that could be introduced onto scaffolds to facilitate optimal binding, which allowed for increased binding with previously uncharacterized regions. MD simulations were used to elucidate primary changes that occur in the Hsp90 C-terminal binding pocket in the presence of first-generation ligands. This data was then used to design ligands that adapt to these receptor conformations, which provides access to an energy landscape that is not visible in a static model. The newly synthesized compounds demonstrated anti-proliferative activity at ~150 nanomolar concentration. The method identified herein may be used to design chemical probes that provide additional information on structural variations of Hsp90 C-terminal binding site.
doi:10.1021/ci4005767
PMCID: PMC4123794  PMID: 24397468
Drug-Design; Flexibility; Allostery; MD simulations; Dynamics-Based Design; Hsp90
5.  Development of a High-Throughput Screening Cancer Cell-Based Luciferase Refolding Assay for Identifying Hsp90 Inhibitors 
Abstract
The 90 kDa heat-shock protein (Hsp90) and other cochaperones allow for proper folding of nascent or misfolded polypeptides. Cancer cells exploit these chaperones by maintaining the stability of mutated and misfolded oncoproteins and allowing them to evade proteosomal degradation. Inhibiting Hsp90 is an attractive strategy for cancer therapy, as the concomitant degradation of multiple oncoproteins may lead to effective anti-neoplastic agents. Unfortunately, early clinical trials have been disappointing with N-terminal Hsp90 inhibitors, as it is unclear whether the problems that plague current Hsp90 inhibitors in clinical trials are related to on-target or off-target activity. One approach to overcome these pitfalls is to identify structurally diverse scaffolds that improve Hsp90 inhibitory activity in the cancer cell milieu. Utilizing a panel of cancer cell lines that express luciferase, we have designed an in-cell Hsp90-dependent luciferase refolding assay. The assay was optimized using previously identified Hsp90 inhibitors and experimental novobiocin analogues against prostate, colon, and lung cancer cell lines. This assay exhibits good interplate precision (% CV), a signal-to-noise ratio (S/N) of ≥7, and an approximate Z-factor ranging from 0.5 to 0.7. Novobiocin analogues that revealed activity in this assay were examined via western blot experiments for client protein degradation, a hallmark of Hsp90 inhibition. Subsequently, a pilot screen was conducted using the Prestwick library, and two compounds, biperiden and ethoxyquin, revealed significant activity. Here, we report the development of an in-cell Hsp90-dependent luciferase refolding assay that is amenable across cancer cell lines for the screening of inhibitors in their specific milieu.
doi:10.1089/adt.2012.498
PMCID: PMC3931435  PMID: 24127661
6.  Synthesis and Structure activity relationships of EGCG Analogues, A Recently Identified Hsp90 Inhibitor 
The Journal of organic chemistry  2013;78(16):7859-7884.
Epigallocatechin-3-gallate (EGCG), the principal polyphenol isolated from green tea, was recently shown to inhibit Hsp90, however structure-activity relationships for this natural product have not yet been produced. Herein, we report the synthesis and biological evaluation of EGCG analogues to establish structure-activity relationships between EGCG and Hsp90. All four rings as well as the linker connecting the C- and the D-rings were systematically investigated, which led to the discovery of compounds that inhibit Hs90 and display improvement in efficacy over EGCG. Anti-proliferative activity of all the analogues was determined against MCF-7 and SKBr3 cell lines and Hsp90 inhibitory activity of four most potent analogues was further evaluated by western blot analyses and degradation of Hsp90-dependent client proteins. Prenyl substituted aryl ester of 3,5-dihydroxychroman-3-ol ring system was identified as novel scaffold that exhibit Hsp90 inhibitory activity.
doi:10.1021/jo401027r
PMCID: PMC4123816  PMID: 23834230
7.  Novobiocin analogues with second-generation noviose surrogates 
Hsp90 is a promising therapeutic target for the treatment of cancer. Novobiocin is the first Hsp90 C-terminal inhibitor ever identified and recent structure-activity relationship studies on the noviose sugar identified several commercially available amines as suitable surrogates. In an effort to further understand this region of the molecule, analogues containing various N′-amino substituents were prepared and evaluated against two breast cancer cell lines for determination of their efficacy. Compound 37j manifested the most potent anti-proliferative activity from these studies and induced Hsp90-dependent client protein degradation at mid nano-molar concentrations.
doi:10.1016/j.bmcl.2012.11.022
PMCID: PMC4123793  PMID: 23234644
Heat shock protein 90; Hsp90 inhibitors; Novobiocin analogues; Breast cancer
8.  High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors 
Biology  2014;3(1):101-138.
Hsp90 has become the target of intensive investigation, as inhibition of its function has the ability to simultaneously incapacitate proteins that function in pathways that represent the six hallmarks of cancer. While a number of Hsp90 inhibitors have made it into clinical trials, a number of short-comings have been noted, such that the search continues for novel Hsp90 inhibitors with superior pharmacological properties. To identify new potential Hsp90 inhibitors, we have utilized a high-throughput assay based on measuring Hsp90-dependent refolding of thermally denatured luciferase to screen natural compound libraries. Over 4,000 compounds were screen with over 100 hits. Data mining of the literature indicated that 51 compounds had physiological effects that Hsp90 inhibitors also exhibit, and/or the ability to downregulate the expression levels of Hsp90-dependent proteins. Of these 51 compounds, seven were previously characterized as Hsp90 inhibitors. Four compounds, anthothecol, garcinol, piplartine, and rottlerin, were further characterized, and the ability of these compounds to inhibit the refolding of luciferase, and reduce the rate of growth of MCF7 breast cancer cells, correlated with their ability to suppress the Hsp90-dependent maturation of the heme-regulated eIF2α kinase, and deplete cultured cells of Hsp90-dependent client proteins. Thus, this screen has identified an additional 44 compounds with known beneficial pharmacological properties, but with unknown mechanisms of action as possible new inhibitors of the Hsp90 chaperone machine.
doi:10.3390/biology3010101
PMCID: PMC4009755  PMID: 24833337
Hsp90; Hsp90 inhibitors; high-throughput screen; natural products libraries
9.  3D-QSAR-Assisted Design, Synthesis, and Evaluation of Novobiocin Analogues 
Hsp90 is an attractive therapeutic target for the treatment of cancer. Extensive structural modifications to novobiocin, the first Hsp90 C-terminal inhibitor discovered, have produced a library of novobiocin analogues and revealed some structure–activity relationships. On the basis of the most potent novobiocin analogues generated from prior studies, a three-dimensional quantitative structure–activity (3D QSAR) model was built. In addition, a new set of novobiocin analogues containing various structural features supported by the 3D QSAR model were synthesized and evaluated against two breast cancer cell lines. Several new inhibitors produced antiproliferative activity at midnanomolar concentrations, which results through Hsp90 inhibition.
doi:10.1021/ml300275g
PMCID: PMC3627542  PMID: 23606927
heat shock protein 90; Hsp90 inhibitors; novobiocin; 3D QSAR; breast cancer
10.  Synthesis of Cruentaren A 
Organic letters  2012;14(24):6242-6245.
Cruentaren A, an antifungal benzolactone produced by the myxobacterium Byssovorax cruenta, is highly cytotoxic against various human cancer cell lines and a highly selective inhibitor of mitochondrial F-ATPase. A convergent and efficient synthesis of cruentaren A is reported, based upon a diastereoselective alkylation, a series of stereoselective aldol reactions utilizing Myers’ pseudoephedrine propionamide, an acyl bromide–mediated esterification and a ring-closing metathesis (RCM) as the key steps. The RCM reaction was applied for the first time towards the total synthesis of cruentaren A, which led to a convergent and efficient synthesis of the natural product.
doi:10.1021/ol302999v
PMCID: PMC3528846  PMID: 23205851
11.  Synthesis and Evaluation of Novologues as C-Terminal Hsp90 Inhibitors with Cytoprotective Activity against Sensory Neuron Glucotoxicity 
Journal of Medicinal Chemistry  2012;55(12):5797-5812.
Compound 2 (KU-32) is a first-generation novologue (a novobiocin-based, C-terminal, heat shock protein 90 (Hsp90) inhibitor), that decreases glucose-induced death of primary sensory neurons and reverses numerous clinical indices of diabetic peripheral neuropathy in mice. The current study sought to exploit the C-terminal binding site of Hsp90 to determine whether the optimization of hydrogen bonding and hydrophobic interactions of second generation novologues could enhance neuroprotective activity. Using a series of substituted phenylboronic acids to replace the coumarin lactone of 2, we identified electronegative atoms placed at the meta-position of the B-ring exhibit improved cytoprotective activity, which is believed to result from favorable interactions with Lys539 in the Hsp90 C-terminal binding pocket. Consistent with these results, a meta-3-fluorophenyl substituted novologue (13b) exhibited a 14-fold lower ED50 compared to 2 for protection against glucose-induced toxicity of primary sensory neurons.
doi:10.1021/jm300544c
PMCID: PMC3390240  PMID: 22702513
12.  Development of a Grp94 inhibitor 
Heat shock protein 90 (Hsp90) represents a promising therapeutic target for the treatment of cancer and other diseases. Unfortunately, results from clinical trials have been disappointing as off-target effects and toxicities have been observed. These detriments may be a consequence of pan-Hsp90 inhibition, as all clinically evaluated Hsp90 inhibitors simultaneously disrupt all four human Hsp90 isoforms. Using a structure-based approach, we designed an inhibitor of Grp94, the ER-resident Hsp90. The effect manifested by compound 2 on several Grp94 and Hsp90α/β (cytosolic isoforms) clients were investigated. Compound 2 prevented intracellular trafficking of the Toll receptor, inhibited the secretion of IGF-II, affected the conformation of Grp94, and suppressed Drosophila larval growth, all Grp94-dependent processes. In contrast, compound 2 had no effect on cell viability or cytosolic Hsp90α/β client proteins at similar concentrations. The design, synthesis, and evaluation of 2 are described herein.
doi:10.1021/ja303477g
PMCID: PMC3414055  PMID: 22642269
13.  The hERG channel is dependent upon the Hsp90α isoform for maturation and trafficking 
Molecular pharmaceutics  2012;9(6):1841-1846.
Heat shock protein 90 (Hsp90) has emerged as a promising therapeutic target for the treatment of cancer. Several Hsp90 inhibitors have entered clinical trials. However, some toxicological detriments have arisen, such as cardiotoxicity resulting from hERG inhibition following the administration of Hsp90 inhibitors. We sought to investigate this toxicity as hERG has been previously reported as a client protein that depends upon Hsp90 for its maturation and functional trafficking. In this study we show that hERG depends upon a single Hsp90 isoform. hERG preferentially co-immunoprecipitated with Hsp90α and genetic knockdown of Hsp90α, but not Hsp90β, resulted in a trafficking-defective hERG channel. This study demonstrates the importance of delineating the isoform dependence of Hsp90 client proteins and provides rationale for the design of isoform-selective Hsp90 inhibitors that avoid detrimental effects.
doi:10.1021/mp300138n
PMCID: PMC3557513  PMID: 22554505
Hsp90; isoform; hERG
14.  3D-QSAR Assisted Design, Synthesis and Evaluation of Novobiocin Analogues 
Hsp90 is an attractive therapeutic target for the treatment of cancer. Extensive structural modifications to novobiocin, the first Hsp90 C-terminal inhibitor discovered, have produced a library of novobiocin analogues and revealed some structure–activity relationships. Based upon the most potent novobiocin analogues generated from prior studies, a three-dimensional quantitative structure-activity (3D-QSAR) model was built. In addition, a new set of novobiocin analogues containing various structural features supported by the 3D-QSAR model were synthesized and evaluated against two breast cancer cell lines. Several new inhibitors produced anti-proliferative activity at mid nano-molar concentrations, which results through Hsp90 inhibition.
doi:10.1021/ml300275g
PMCID: PMC3627542  PMID: 23606927
Heat shock protein 90; Hsp90 inhibitors; Novobiocin; 3D-QSAR; Breast cancer
15.  Optimization of Potent Hepatitis C Virus NS3 Helicase Inhibitors Isolated from the Yellow Dyes Thioflavine S and Primuline 
Journal of medicinal chemistry  2012;55(7):3319-3330.
A screen for hepatitis C virus (HCV) NS3 helicase inhibitors revealed that the commercial dye thioflavine S was the most potent inhibitor of NS3-catalyzed DNA and RNA unwinding in the 827-compound National Cancer Institute Mechanistic Set. Thioflavine S and the related dye primuline were separated here into their pure components, all of which were oligomers of substituted benzothiazoles. The most potent compound (P4), a benzothiazole tetramer, inhibited unwinding >50% at 2±1 μM, inhibited the subgenomic HCV replicon at 10 μM, and was not toxic at 100 μM. Because P4 also interacted with DNA, more specific analogs were synthesized from the abundant dimeric component of primuline. Some of the 29 analogs prepared retained ability to inhibit HCV helicase but did not appear to interact with DNA. The most potent of these specific helicase inhibitors (compound 17) was active against the replicon and inhibited the helicase more than 50% at 2.6±1 μM.
doi:10.1021/jm300021v
PMCID: PMC3476947  PMID: 22409723
Hepatitis C virus; NS3; helicase; protease; ATPase; benzothiazoles
16.  3-Arylcoumarin derivatives manifest anti-proliferative activity through Hsp90 inhibition 
ACS medicinal chemistry letters  2012;3(4):327-331.
The potential therapeutic benefits associated with Hsp90 modulation for the treatment of cancer and neurodegenerative diseases highlight the importance of identifying novel Hsp90 scaffolds. KU-398, a novobiocin analogue, and silybin were recently identified as new Hsp90 inhibitors. Consequently, a library of 3-arylcoumarin derivatives that incorporated the structural features of KU-398 and silybin was designed, synthesized and evaluated against two breast cancer cell lines. Western blot analysis confirmed that the resulting 3-arylcoumarin hybrids target the Hsp90 protein folding machinery.
doi:10.1021/ml300018e
PMCID: PMC3539803  PMID: 23316269
Heat shock protein 90; Hsp90 inhibitors; Novobiocin; Silybin; 3-Arylcoumarin; Breast cancer
17.  3-Arylcoumarin Derivatives Manifest Anti-proliferative Activity through Hsp90 Inhibition 
ACS Medicinal Chemistry Letters  2012;3(4):327-331.
The potential therapeutic benefits associated with Hsp90 modulation for the treatment of cancer and neurodegenerative diseases highlight the importance of identifying novel Hsp90 scaffolds. KU-398, a novobiocin analogue, and silybin were recently identified as new Hsp90 inhibitors. Consequently, a library of 3-arylcoumarin derivatives that incorporated the structural features of KU-398 and silybin was designed, synthesized, and evaluated against two breast cancer cell lines. Western blot analysis confirmed that the resulting 3-arylcoumarin hybrids target the Hsp90 protein folding machinery.
doi:10.1021/ml300018e
PMCID: PMC3539803  PMID: 23316269
heat shock protein 90; Hsp90 inhibitors; novobiocin; silybin; 3-arylcoumarin; breast cancer
18.  Synthesis and biological evaluation of arylated novobiocin analogs as Hsp90 inhibitors 
Novobiocin analogs lacking labile glycosidic ether have been designed, synthesized and evaluated for Hsp90 inhibitory activity. Replacement of the synthetically complex noviose sugar with simple aromatic side chains produced analogs that maintain moderate cytotoxic activity against MCF7 and SkBR3 breast cancer cell-lines. Rationale for the preparation of des-noviose novobiocin analogs in addition to their synthesis and biological evaluation are presented herein.
doi:10.1016/j.bmcl.2011.09.073
PMCID: PMC3242434  PMID: 22014546
19.  KU-32, a Novel Drug for Diabetic Neuropathy, Is Safe for Human Islets and Improves In Vitro Insulin Secretion and Viability 
Experimental Diabetes Research  2012;2012:671673.
KU-32 is a novel, novobiocin-based Hsp90 inhibitor that protects against neuronal glucotoxicity and reverses multiple clinical indices of diabetic peripheral neuropathy in a rodent model. However, any drug with potential for treating diabetic complications must also have no adverse effects on the function of pancreatic islets. Thus, the goal of the current study was to assess the effect of KU-32 on the in vitro viability and function of human islets. Treating human islets with KU-32 for 24 hours showed no toxicity as assessed using the alamarBlue assay. Confocal microscopy confirmed that with a minimum of 2-day exposure, KU-32 improved cellular viability by blocking apoptosis. Functionally, isolated human islets released more glucose-stimulated insulin when preincubated in KU-32. However, diabetic BKS-db/db mice, a model for type 2 diabetes, administered KU-32 for 10 weeks did not show any significant changes in blood glucose and insulin levels, despite having greater insulin staining/beta cell in the pancreas compared to untreated BKS db/db mice. In summary, KU-32 did not harm isolated human islets and may even be protective. However, the effect does not appear significant enough to alter the in vivo metabolic parameters of diabetic mice.
doi:10.1155/2012/671673
PMCID: PMC3503326  PMID: 23197975
20.  Monoenomycin: A Simplified Trienomycin A Analogue that Manifests Anticancer Activity 
ACS medicinal chemistry letters  2011;2(10):735-740.
Macrocyclic natural products are a powerful class of lead-like chemical entities. Despite commonly violating Lipinski’s “rule of 5”, these compounds often demonstrate superior drug-like physicochemical and pharmacokinetic attributes when compared to their acyclic counterparts. However, the elaborate structural architectures of such molecules require rigorous synthetic investigation that complicates analogue development and their application to drug discovery programs. To circumvent these limitations, a conformation-based approach using limited SAR and molecular modeling was implemented to design simplified analogues of trienomycin A, in which the corresponding analogues could be prepared in a succinct manner to rapidly identify essential structural components necessary for biological activity. Trienomycin A is a member of the ansamycin family of natural products that possesses potent anticancer activity. These studies revealed a novel trienomycin A analogue, monoenomycin, which manifests potent anticancer activity.
doi:10.1021/ml200108y
PMCID: PMC3230222  PMID: 22162786
Trienomycin A; Conformation; Anticancer; Ansamycin synthesis; Structure-activity relationship
21.  Monoenomycin: A Simplified Trienomycin A Analogue That Manifests Anticancer Activity 
ACS Medicinal Chemistry Letters  2011;2(10):735-740.
Macrocyclic natural products are a powerful class of leadlike chemical entities. Despite commonly violating Lipinski's “rule of 5”, these compounds often demonstrate superior druglike physicochemical and pharmacokinetic attributes when compared to their acyclic counterparts. However, the elaborate structural architectures of such molecules require rigorous synthetic investigation that complicates analogue development and their application to drug discovery programs. To circumvent these limitations, a conformation-based approach using limited structure–activity relationships and molecular modeling was implemented to design simplified analogues of trienomycin A, in which the corresponding analogues could be prepared in a succinct manner to rapidly identify essential structural components necessary for biological activity. Trienomycin A is a member of the ansamycin family of natural products that possesses potent anticancer activity. These studies revealed a novel trienomycin A analogue, monoenomycin, which manifests potent anticancer activity.
doi:10.1021/ml200108y
PMCID: PMC3230222  PMID: 22162786
Trienomycin A; conformation; anticancer; ansamycin synthesis; structure−activity relationship
22.  Targeting the Heat Shock Protein 90 Dimer with Dimeric Inhibitors 
Journal of medicinal chemistry  2011;54(18):6234-6253.
The design, synthesis and biological evaluation of conformationally constrained coumermycin A1 analogues are reported. Compounds were evaluated against both breast cancer (SKBr3 and MCF7) and prostate cancer (PC3mm2, A549 and HT29) cell lines. Non-noviosylated coumermycin A1 analogues that manifest potent anti-proliferative activity resulting from Hsp90 inhibition are provided, wherein replacement of the stereochemically complex noviose sugar with readily available piperidine rings resulted in ~100 fold increase in anti-proliferative activities as compared to coumermycin A1, producing small molecule Hsp90 inhibitors that exhibit nanomolar activities.
doi:10.1021/jm200553w
PMCID: PMC3184553  PMID: 21861487
23.  Elucidation of the Hsp90 C-terminal Inhibitor Binding Site 
ACS chemical biology  2011;6(8):800-807.
The Hsp90 chaperone machine is required for the folding, activation and/or stabilization of more than 50 proteins directly related to malignant progression. Hsp90 contains small molecule binding sites at both its N- and C-terminal domains, however, limited structural and biochemical data regarding the C-terminal binding site is available. In this report, the small molecule binding site in the Hsp90 C-terminal domain was revealed by protease fingerprinting and photoaffinity labeling utilizing LC-MS/MS. The identified site was characterized by generation of a homology model for hHsp90α using the SAXS open structure of HtpG and docking the bioactive conformation of NB into the generated model. The resulting model for the bioactive conformation of NB bound to Hsp90α is presented herein.
doi:10.1021/cb200052x
PMCID: PMC3164513  PMID: 21548602
24.  Engineering an Antibiotic to Fight Cancer: Optimization of the Novobiocin Scaffold to Produce Anti-Proliferative Agents 
Journal of medicinal chemistry  2011;54(11):3839-3853.
Development of the DNA gyrase inhibitor, novobiocin, into a selective Hsp90 inhibitor was accomplished through structural modifications to the amide side chain, coumarin ring, and sugar moiety. These species exhibit ~700-fold improved anti-proliferative activity versus the natural product as evaluated by cellular efficacies against breast, colon, prostate, lung, and other cancer cell lines. Utilization of structure–activity relationships established for three novobiocin synthons produced optimized scaffolds, which manifest mid-nanomolar activity against a panel of cancer cell lines and serve as lead compounds that manifest their activities through Hsp90 inhibition.
doi:10.1021/jm200148p
PMCID: PMC3164572  PMID: 21553822
25.  Gambogic Acid, a Natural Product Inhibitor of Hsp90 
Journal of natural products  2011;74(5):1085-1092.
A high-throughput screening of natural product libraries identified (−)-gambogic acid (1), a component of the exudate of Garcinia harburyi, as a potential Hsp90 inhibitor, in addition to the known Hsp90 inhibitor celastrol (2). Subsequent testing established that 1 inhibited cell proliferation, brought about the degradation of Hsp90 client proteins in cultured cells, and induced the expression of Hsp70 and Hsp90, which are hallmarks of Hsp90 inhibition. Gambogic acid also disrupted the interaction of Hsp90, Hsp70 and Cdc37 with the heme-regulated eIF2α kinase (HRI- an Hsp90-dependent client) and blocked the maturation of HRI in vitro. Surface plasmon resonance spectroscopy indicated that 1 bound to the N-terminal domain of Hsp90 with a low micromolar Kd, in a manner that was not competitive with the Hsp90 inhibitor geldanamycin (3). Molecular docking experiments supported the posit that 1 binds Hsp90 at a site distinct from Hsp90’s ATP binding pocket. The data obtained have firmly established 1 as a novel Hsp90 inhibitor and have provided evidence of a new site that can be targeted for the development of improved Hsp90 inhibitors.
doi:10.1021/np200029q
PMCID: PMC3103600  PMID: 21486005

Results 1-25 (55)