Publications by authors named "Alexander Bolaender"

16 Publications

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The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction.

Nat Commun 2020 01 16;11(1):319. Epub 2020 Jan 16.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.
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http://dx.doi.org/10.1038/s41467-019-14082-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965647PMC
January 2020

Paradigms for Precision Medicine in Epichaperome Cancer Therapy.

Cancer Cell 2019 11 24;36(5):559-573.e7. Epub 2019 Oct 24.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Program in Molecular Pharmacology, Sloan Kettering Institute, New York, NY 10065, USA.

Alterations in protein-protein interaction networks are at the core of malignant transformation but have yet to be translated into appropriate diagnostic tools. We make use of the kinetic selectivity properties of an imaging probe to visualize and measure the epichaperome, a pathologic protein-protein interaction network. We are able to assay and image epichaperome networks in cancer and their engagement by inhibitor in patients' tumors at single-lesion resolution in real time, and demonstrate that quantitative evaluation at the level of individual tumors can be used to optimize dose and schedule selection. We thus provide preclinical and clinical evidence in the use of this theranostic platform for precision medicine targeting of the aberrant properties of protein networks.
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http://dx.doi.org/10.1016/j.ccell.2019.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996250PMC
November 2019

A Chemical Biology Approach to the Chaperome in Cancer-HSP90 and Beyond.

Cold Spring Harb Perspect Biol 2020 04 1;12(4). Epub 2020 Apr 1.

Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065.

Cancer is often associated with alterations in the chaperome, a collection of chaperones, cochaperones, and other cofactors. Changes in the expression levels of components of the chaperome, in the interaction strength among chaperome components, alterations in chaperome constituency, and in the cellular location of chaperome members, are all hallmarks of cancer. Here we aim to provide an overview on how chemical biology has played a role in deciphering such complexity in the biology of the chaperome in cancer and in other diseases. The focus here is narrow and on pathologic changes in the chaperome executed by enhancing the interaction strength between components of distinct chaperome pathways, specifically between those of HSP90 and HSP70 pathways. We will review chemical tools and chemical probe-based assays, with a focus on HSP90. We will discuss how kinetic binding, not classical equilibrium binding, is most appropriate in the development of drugs and probes for the chaperome in disease. We will then present our view on how chaperome inhibitors may become potential drugs and diagnostics in cancer.
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http://dx.doi.org/10.1101/cshperspect.a034116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773535PMC
April 2020

HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons.

Nat Commun 2018 10 19;9(1):4345. Epub 2018 Oct 19.

The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 256, New York, NY, 10065, USA.

Environmental and genetic risk factors contribute to Parkinson's Disease (PD) pathogenesis and the associated midbrain dopamine (mDA) neuron loss. Here, we identify early PD pathogenic events by developing methodology that utilizes recent innovations in human pluripotent stem cells (hPSC) and chemical sensors of HSP90-incorporating chaperome networks. We show that events triggered by PD-related genetic or toxic stimuli alter the neuronal proteome, thereby altering the stress-specific chaperome networks, which produce changes detected by chemical sensors. Through this method we identify STAT3 and NF-κB signaling activation as examples of genetic stress, and phospho-tyrosine hydroxylase (TH) activation as an example of toxic stress-induced pathways in PD neurons. Importantly, pharmacological inhibition of the stress chaperome network reversed abnormal phospho-STAT3 signaling and phospho-TH-related dopamine levels and rescued PD neuron viability. The use of chemical sensors of chaperome networks on hPSC-derived lineages may present a general strategy to identify molecular events associated with neurodegenerative diseases.
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http://dx.doi.org/10.1038/s41467-018-06486-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195591PMC
October 2018

Targetable Clinical Nanoparticles for Precision Cancer Therapy Based on Disease-Specific Molecular Inflection Points.

Nano Lett 2017 11 23;17(11):7160-7168. Epub 2017 Oct 23.

Departments of Pharmacology and Radiology, Weill Cornell Medical College , New York, New York 10065, United States.

Novel translational approaches based on clinical modular nanoplatforms are needed in order to treat solid cancers according to their discrete molecular features. In the present study, we show that the clinical nanopharmaceutical Ferumoxytol, which consists of a glucose-based coat surrounding an iron oxide core, could identify molecular characteristics of prostate cancer, corresponding to unique phases of the disease continuum. By affixing a targeting probe for the prostate-specific membrane antigen on its surface, the nanopharmaceutical was able to assess the functional state of the androgen receptor pathway via MRI, guiding therapy and delivering it with the same clinical nanoparticle. In order to simultaneously inhibit signaling from key oncogenic pathways of more advanced forms of prostate cancer, a single-agent therapy for early stage disease to inhibit DNA replication, as well as combination therapy with two drugs co-retained within the nanopharmaceutical's polymeric coating, were tested and resulted in complete tumor ablation. Recalcitrant and terminal forms of the disease were effectively treated with a nanopharmaceutical delivering a combination that upregulates endoplasmic reticulum stress and inhibits metastasis, thereby showing that this multifunctional nanoplatform can be used in the clinic for patient stratification, as well as precision treatment based on the individual's unique disease features.
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http://dx.doi.org/10.1021/acs.nanolett.7b04209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677550PMC
November 2017

Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma.

Mol Cancer Ther 2017 09 15;16(9):1779-1790. Epub 2017 Jun 15.

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.

Hsp90 is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells. Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome, which maintains the malignant phenotype in the setting of MYC. Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation. In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity and , including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR inhibition and Overall, this work provides support for Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. .
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587381PMC
September 2017

Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.

J Clin Invest 2016 11 26;126(11):4119-4124. Epub 2016 Sep 26.

Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer. Although the MEK inhibitor selumetinib transiently inhibited ERK signaling, which subsequently rebounded, the MEK inhibitor CKI suppressed ERK signaling in a sustained manner by preventing RAF reactivation. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to RAI therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer.
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http://dx.doi.org/10.1172/JCI89067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096947PMC
November 2016

The epichaperome is an integrated chaperome network that facilitates tumour survival.

Nature 2016 Oct 5;538(7625):397-401. Epub 2016 Oct 5.

Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically 'rewired' to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.
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http://dx.doi.org/10.1038/nature19807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283383PMC
October 2016

Stressing Out Hsp90 in Neurotoxic Proteinopathies.

Curr Top Med Chem 2016 ;16(25):2829-38

Program in Chemical Biology, Memorial Sloan-Kettering Cancer Center, New York, USA.

A toxic accumulation of proteins is the hallmark pathology of several neurodegenerative disorders. Protein accumulation is regularly prevented by the network of molecular chaperone proteins, including and especially Hsp90. For reasons not yet elucidated, Hsp90 and the molecular chaperones interact with, but do not degrade, these toxic proteins resulting in the pathogenic accumulation of proteins such as tau, in Alzheimer's Disease, and α-synuclein, in Parkinson's Disease. In this review, we describe the associations between Hsp90 and the pathogenic and driver proteins of several neurodegenerative disorders. We additionally describe how the inhibition of Hsp90 promotes the degradation of both mutant and pathogenic protein species in models of neurodegenerative diseases. We also examine the current state of Hsp90 inhibitors capable of crossing the blood-brain barrier; compounds which may be capable of slowing, preventing, and possible reversing neurodegenerative diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995127PMC
http://dx.doi.org/10.2174/1568026616666160413141350DOI Listing
February 2017

Heat Shock Protein (HSP) Drug Discovery and Development: Targeting Heat Shock Proteins in Disease.

Curr Top Med Chem 2016 ;16(25):2753-64

Program in Chemical Biology, Sloan Kettering Institute, New York, NY 10021, USA.

Heat shock proteins (HSPs) present as a double edged sword. While they play an important role in maintaining protein homeostasis in a normal cell, cancer cells have evolved to co-opt HSP function to promote their own survival. As a result, HSPs such as HSP90 have attracted a great deal of interest as a potential anticancer target. These efforts have resulted in over 20 distinct compounds entering clinical evaluation for the treatment of cancer. However, despite the potent anticancer activity demonstrated in preclinical models, to date no HSP90 inhibitor has obtained regulatory approval. In this review we discuss the unique challenges faced in targeting HSPs that have likely contributed to their lack of progress in the clinic and suggest ways to overcome these so that the enormous potential of these compounds to benefit patients can finally be realized. We also provide a guideline for the future development of HSP-targeted agents based on the many lessons learned during the last two decades in developing HSP90 inhibitors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995156PMC
http://dx.doi.org/10.2174/1568026616666160413141911DOI Listing
February 2017

Radiosynthesis of the iodine-124 labeled Hsp90 inhibitor PU-H71.

J Labelled Comp Radiopharm 2016 Mar 25;59(3):129-32. Epub 2016 Jan 25.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Heat shock protein 90 (Hsp90) is an ATP dependent molecular chaperone protein whose function is critical for maintaining several key proteins involved in survival and proliferation of cancer cells. PU-H71 (1), is a potent purine-scaffold based ATP pocket binding Hsp90 inhibitor which has been shown to have potent activity in a broad range of in vivo cancer models and is currently in Phase I clinical trials in patients with advanced solid malignancies, lymphomas, and myeloproliferative neoplasms. In this report, we describe the radiosynthesis of [(124)I]-PU-H71(5); this was synthesized from the corresponding Boc-protected stannane precursor 3 by iododestannylation with [(124)I]-NaI using chloramine-T as an oxidant for 2 min, followed by Boc deprotection with 6 N HCl at 50 °C for 30 min to yield the final compound. The final product 5 was purified using HPLC and was isolated with an overall yield of 55 ± 6% (n = 6, isolated) from 3, and >98% purity and an average specific activity of 980 mCi/µmol. Our report sets the stage for the introduction of [(124)I]-PU-H71 as a potential non-invasive probe for understanding biodistribution and pharmacokinetics of PU-H71 in living subjects using positron emission tomography imaging.
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http://dx.doi.org/10.1002/jlcr.3369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779400PMC
March 2016

Multifunctional MRI/PET Nanobeacons Derived from the in Situ Self-Assembly of Translational Polymers and Clinical Cargo through Coalescent Intermolecular Forces.

Nano Lett 2015 Dec 11;15(12):8032-43. Epub 2015 Nov 11.

Department of Chemistry, Hunter College and Graduate Center of the City University of New York , New York, New York 10065, United States.

Novel multifunctional platforms are needed for oncology in order to assist physicians during surgery and chemotherapy. In the present study, we show that polymeric nanobeacons, consisting of the glucose-based polymer dextran, can be used to guide surgery and improve drug delivery. For imaging, the nanobeacons stably retained the positron emitter 89-zirconium and the MRI contrast agent gadolinium, without the need of a chelator. In addition to using them for PET imaging, the (89)Zr-nanobeacons guided the surgical resection of sentinel lymph nodes, utilizing their inherent Cerenkov luminescence. Through weak electrostatic interactions, the nanoparticles carried combinations of chemotherapeutics for the simultaneous inhibition of oncogenic pathways, resulting in enhanced tumor regression. The nanobeacons also allowed monitoring of drug release via MRI, through the quenching of the gadolinium signal by the coloaded drug, making them a new multifunctional theranostic nanotechnology platform for the clinic.
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http://dx.doi.org/10.1021/acs.nanolett.5b03370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703344PMC
December 2015

Non-invasive PET Imaging of PARP1 Expression in Glioblastoma Models.

Mol Imaging Biol 2016 06;18(3):386-92

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York City, NY, 10065, USA.

Purpose: The current study presents [(18)F]PARPi as imaging agent for PARP1 expression.

Procedures: [(18)F]PARPi was generated by conjugating a 2H-phthalazin-1-one scaffold to 4-[(18)F]fluorobenzoic acid. Biochemical assays, optical in vivo competition, biodistribution analysis, positron emission tomography (PET)/X-ray computed tomography, and PET/magnetic resonance imaging studies were performed in subcutaneous and orthotopic mouse models of glioblastoma.

Results: [(18)F]PARPi shows suitable pharmacokinetic properties for brain tumor imaging (IC50 = 2.8 ± 1.1 nM; logPCHI = 2.15 ± 0.41; plasma-free fraction = 63.9 ± 12.6 %) and accumulates selectively in orthotopic brain tumor tissue. Tracer accumulation in subcutaneous brain tumors was 1.82 ± 0.21 %ID/g, whereas in healthy brain, the uptake was only 0.04 ± 0.01 %ID/g.

Conclusions: [(18)F]PARPi is a selective PARP1 imaging agent that can be used to visualize glioblastoma in xenograft and orthotopic mouse models with high precision and good signal/noise ratios. It offers new opportunities to non-invasively image tumor growth and monitor interventions.
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http://dx.doi.org/10.1007/s11307-015-0904-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841747PMC
June 2016

Radioiodinated PARP1 tracers for glioblastoma imaging.

EJNMMI Res 2015 Dec 4;5(1):123. Epub 2015 Sep 4.

Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Background: Although the understanding of the genetic and molecular basis of cancer has advanced significantly over the past several decades, imaging and treatment options for glioblastoma patients have been more limited (N Engl J Med 359:492-507, 2008). This is in part due to difficulties in diagnosing this disease early, combined with its diffuse, infiltrative growth. This study was aimed at the development of a novel diagnostic tool for glioblastoma through the synthesis of a small molecule based on radioiodinated poly(ADP-ribose)polymerase 1 (PARP1) targeted tracers. This PARP1 is a biomarker that is overexpressed in glioblastoma tissue, but has only low expression levels in the healthy brain (Neoplasia 16:432-40, 2014).

Methods: A library of PARP1 inhibitors (iodo-PARPis) was synthesized. Based on their pharmacokinetic properties and nuclear PARP1 binding, the most successful inhibitor was radiolabeled with (131)I and (124)I. Biodistribution as well as imaging experiments were performed in orthotopic and subcutaneous mouse models of glioblastoma.

Results: One member of our iodo-poly(ADP-ribose)polymerase 1 (PARP1) inhibitor library, I2-PARPi, shows promising biophysical properties for in vivo application. All synthesized tracers have IC50 values in the nanomolar range (9 ± 2-107 ± 4 nM) and were able to inhibit the uptake of a fluorescent PARP1 inhibitor analog (PARPi-FL). I2-PARPi was able to reduce the uptake of PARPi-FL by 78 ± 4 % in vivo. In mouse models of glioblastoma, we show that the radioiodinated inhibitor analog has high uptake in tumor tissue (U251 MG xenograft, tumor, 0.43 ± 0.06 %ID/g; brain, 0.01 ± 0.00 %ID/g; muscle, 0.03 ± 0.01 %ID/g; liver, 2.35 ± 0.57 %ID/g; thyroid, 0.24 ± 0.06 %ID/g). PET and SPECT imaging performed in orthotopic glioblastoma models with [(124)I]- and [(131)I]-I2-PARPi showed selective accumulation in the tumor tissue. These results were also verified using autoradiography of tumor sections, which displayed focal selective uptake of the tracer in the tumor regions as confirmed by histology. The uptake could be blocked through pre-injection of excess unlabeled PARP1 inhibitor (Olaparib).

Conclusions: We have successfully synthesized and radioiodinated the PARP1 selective tracer I2-PARPi. The novel tracer shows selective binding to tumor tissue, both in vitro and in models of glioblastoma, and has the potential to serve as a selective PET imaging agent for brain tumors.
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http://dx.doi.org/10.1186/s13550-015-0123-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559561PMC
December 2015

Structure-activity relationship in a purine-scaffold compound series with selectivity for the endoplasmic reticulum Hsp90 paralog Grp94.

J Med Chem 2015 May 22;58(9):3922-43. Epub 2015 Apr 22.

†Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York 10021, United States.

Grp94 is involved in the regulation of a restricted number of proteins and represents a potential target in a host of diseases, including cancer, septic shock, autoimmune diseases, chronic inflammatory conditions, diabetes, coronary thrombosis, and stroke. We have recently identified a novel allosteric pocket located in the Grp94 N-terminal binding site that can be used to design ligands with a 2-log selectivity over the other Hsp90 paralogs. Here we perform extensive SAR investigations in this ligand series and rationalize the affinity and paralog selectivity of choice derivatives by molecular modeling. We then use this to design 18c, a derivative with good potency for Grp94 (IC50 = 0.22 μM) and selectivity over other paralogs (>100- and 33-fold for Hsp90α/β and Trap-1, respectively). The paralog selectivity and target-mediated activity of 18c was confirmed in cells through several functional readouts. Compound 18c was also inert when tested against a large panel of kinases. We show that 18c has biological activity in several cellular models of inflammation and cancer and also present here for the first time the in vivo profile of a Grp94 inhibitor.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518544PMC
May 2015

Protein chaperones: a composition of matter review (2008 - 2013).

Expert Opin Ther Pat 2014 May;24(5):501-18

Memorial Sloan-Kettering Cancer Center, Program in Molecular Pharmacology and Chemistry and Department of Medicine , NY , USA.

Introduction: Heat shock proteins (Hsps) are proteins with important functions in regulating disease phenotypes. Historically, Hsp90 has first received recognition as a target in cancer, with consequent efforts extending its potential role to other diseases. Hsp70 has also attracted interest as a therapeutic target for its role as a co-chaperone to Hsp90 as well as its own anti-apoptotic roles.

Areas Covered: Herein, patents from 2008 to 2013 are reviewed to identify those that disclose composition of matter claimed to inhibit Hsp90 or Hsp70.

Expert Opinion: For Hsp90, there has been considerable creativity in the discovery of novel pharmacophores that fall outside the three initially discovered scaffolds (i.e., ansamycins, resorcinols and purines). Nonetheless, much of the patent literature appears to build on previously reported structure activity relationship through slight modifications of Hsp90 inhibitor space by finding weaknesses in existing patents. The major goal of future development of Hsp90 inhibitors is not necessarily identifying better molecules but rather understanding how to rationally use these agents in the clinic. The development of Hsp70 inhibitors has lagged behind. It will require a more concerted effort from the drug discovery community in order to begin to realize the potential of this target.
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http://dx.doi.org/10.1517/13543776.2014.887681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124460PMC
May 2014