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428 results on '"Neckers, Len"'

2. Second Virtual International Symposium on Cellular and Organismal Stress Responses, September 8–9, 2022

Author

van Oosten-Hawle, Patricija, Backe, Sarah J., Ben-Zvi, Anat, Bourboulia, Dimitra, Brancaccio, Mara, Brodsky, Jeff, Clark, Melody, Colombo, Giorgio, Cox, Marc B., De Los Rios, Paolo, Echtenkamp, Frank, Edkins, Adrienne, Freeman, Brian, Goloubinoff, Pierre, Houry, Walid, Johnson, Jill, LaPointe, Paul, Li, Wei, Mezger, Valerie, Neckers, Len, Nillegoda, Nadinath B., Prahlad, Veena, Reitzel, Adam, Scherz-Shouval, Ruth, Sistonen, Lea, Tsai, Francis T. F., Woodford, Mark R., Mollapour, Mehdi, and Truman, Andrew W.

Published
2023

3. Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer

Author

Shkedi, Arielle, Taylor, Isabelle R, Echtenkamp, Frank, Ramkumar, Poornima, Alshalalfa, Mohamed, Rivera-Márquez, Génesis M, Moses, Michael A, Shao, Hao, Karnes, Robert Jeffrey, Neckers, Len, Feng, Felix, Kampmann, Martin, and Gestwicki, Jason E

Subjects
Biochemistry and Cell Biology, Biological Sciences, Urologic Diseases, Clinical Research, Aging, Prostate Cancer, Cancer, Aetiology, 2.1 Biological and endogenous factors, Cell Line, Tumor, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Humans, Male, Molecular Chaperones, Prostatic Neoplasms, Castration-Resistant, Proteostasis, Receptors, Androgen, chaperones, functional genomics, heat shock proteins, mitochondria, prostate cancer, proteostasis, shRNA, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

Castration-resistant prostate cancer (CRPC) is associated with an increased reliance on heat shock protein 70 (HSP70), but it is not clear what other protein homeostasis (proteostasis) factors might be involved. To address this question, we performed functional and synthetic lethal screens in four prostate cancer cell lines. These screens confirmed key roles for HSP70, HSP90, and their co-chaperones, but also suggested that the mitochondrial chaperone, HSP60/HSPD1, is selectively required in CRPC cell lines. Knockdown of HSP60 does not impact the stability of androgen receptor (AR) or its variants; rather, it is associated with loss of mitochondrial spare respiratory capacity, partly owing to increased proton leakage. Finally, transcriptional data revealed a correlation between HSP60 levels and poor survival of prostate cancer patients. These findings suggest that re-wiring of the proteostasis network is associated with CRPC, creating selective vulnerabilities that might be targeted to treat the disease.

Published
2022

6. Exploration of Benzothiazole Rhodacyanines as Allosteric Inhibitors of Protein-Protein Interactions with Heat Shock Protein 70 (Hsp70).

Author

Shao, Hao, Li, Xiaokai, Moses, Michael A, Gilbert, Luke A, Kalyanaraman, Chakrapani, Young, Zapporah T, Chernova, Margarita, Journey, Sara N, Weissman, Jonathan S, Hann, Byron, Jacobson, Matthew P, Neckers, Len, and Gestwicki, Jason E

Subjects
Cell Line, Tumor, Animals, Humans, Mice, Pyridinium Compounds, Thiazoles, Allosteric Regulation, Protein Conformation, Protein Binding, Structure-Activity Relationship, Drug Design, Female, HSP70 Heat-Shock Proteins, Benzothiazoles, MCF-7 Cells, Molecular Docking Simulation, Cancer, Aging, Breast Cancer, Medicinal and Biomolecular Chemistry, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry
Abstract

Cancer cells rely on the chaperone heat shock protein 70 (Hsp70) for survival and proliferation. Recently, benzothiazole rhodacyanines have been shown to bind an allosteric site on Hsp70, interrupting its binding to nucleotide-exchange factors (NEFs) and promoting cell death in breast cancer cell lines. However, proof-of-concept molecules, such as JG-98, have relatively modest potency (EC50 ≈ 0.7-0.4 μM) and are rapidly metabolized in animals. Here, we explored this chemical series through structure- and property-based design of ∼300 analogs, showing that the most potent had >10-fold improved EC50 values (∼0.05 to 0.03 μM) against two breast cancer cells. Biomarkers and whole genome CRISPRi screens confirmed members of the Hsp70 family as cellular targets. On the basis of these results, JG-231 was found to reduce tumor burden in an MDA-MB-231 xenograft model (4 mg/kg, ip). Together, these studies support the hypothesis that Hsp70 may be a promising target for anticancer therapeutics.

Published
2018

7. Phase 1 study of the HSP90 inhibitor onalespib in combination with AT7519, a pan-CDK inhibitor, in patients with advanced solid tumors

Author

Do, Khanh T., O’Sullivan Coyne, Geraldine, Hays, John L., Supko, Jeffrey G., Liu, Stephen V., Beebe, Kristin, Neckers, Len, Trepel, Jane B., Lee, Min-Jung, Smyth, Tomoko, Gannon, Courtney, Hedglin, Jennifer, Muzikansky, Alona, Campos, Susana, Lyons, John, Ivy, Percy, Doroshow, James H., Chen, Alice P., and Shapiro, Geoffrey I.

Published
2020
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9. Activation of Hsp90 Enzymatic Activity and Conformational Dynamics through Rationally Designed Allosteric Ligands

Author

Sattin, Sara, Tao, Jiahui, Vettoretti, Gerolamo, Moroni, Elisabetta, Pennati, Marzia, Lopergolo, Alessia, Morelli, Laura, Bugatti, Antonella, Zuehlke, Abbey, Moses, Mike, Prince, Thomas, Kijima, Toshiki, Beebe, Kristin, Rusnati, Marco, Neckers, Len, Zaffaroni, Nadia, Agard, David A, Bernardi, Anna, and Colombo, Giorgio

Subjects
Biotechnology, Cancer, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Adenosine Triphosphatases, Adenosine Triphosphate, Allosteric Site, Benzofurans, Biochemical Phenomena, Cell Line, Tumor, Chaperonins, HSP90 Heat-Shock Proteins, Humans, Hydrolysis, Ligands, Protein Binding, Protein Conformation, allostery, drug design, functional dynamics, glycoconjugates, Hsp90, Chemical Sciences, General Chemistry
Abstract

Hsp90 is a molecular chaperone of pivotal importance for multiple cell pathways. ATP-regulated internal dynamics are critical for its function and current pharmacological approaches block the chaperone with ATP-competitive inhibitors. Herein, a general approach to perturb Hsp90 through design of new allosteric ligands aimed at modulating its functional dynamics is proposed. Based on the characterization of a first set of 2-phenylbenzofurans showing stimulatory effects on Hsp90 ATPase and conformational dynamics, new ligands were developed that activate Hsp90 by targeting an allosteric site, located 65 Å from the active site. Specifically, analysis of protein responses to first-generation activators was exploited to guide the design of novel derivatives with improved ability to stimulate ATP hydrolysis. The molecules' effects on Hsp90 enzymatic, conformational, co-chaperone and client-binding properties were characterized through biochemical, biophysical and cellular approaches. These designed probes act as allosteric activators of the chaperone and affect the viability of cancer cell lines for which proper functioning of Hsp90 is necessary.

Published
2015

20. Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors

Author

Do, Khanh, Speranza, Giovanna, Chang, Lun-Ching, Polley, Eric C., Bishop, Rachel, Zhu, Weimin, Trepel, Jane B., Lee, Sunmin, Lee, Min-Jung, Kinders, Robert J., Phillips, Larry, Collins, Jerry, Lyons, John, Jeong, Woondong, Antony, Ramya, Chen, Alice P., Neckers, Len, Doroshow, James H., and Kummar, Shivaani

Published
2015
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26. UOK 262 cell line, fumarate hydratase deficient ( FH−/ FH−) hereditary leiomyomatosis renal cell carcinoma: in vitro and in vivo model of an aberrant energy metabolic pathway in human cancer

Author

Yang, Youfeng, Valera, Vladimir A., Padilla-Nash, Hesed M., Sourbier, Carole, Vocke, Cathy D., Vira, Manish A., Abu-Asab, Mones S., Bratslavsky, Gennady, Tsokos, Maria, Merino, Maria J., Pinto, Peter A., Srinivasan, Ramaprasad, Ried, Thomas, Neckers, Len, and Linehan, W. Marston

Published
2010
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32. The complex dance of the molecular chaperone Hsp90

Author

Neckers, Len, Mollapour, Mehdi, and Tsutsumi, Shinji

Subjects
Heat shock proteins, Biological sciences, Chemistry
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tibs.2009.01.006 Byline: Len Neckers, Mehdi Mollapour, Shinji Tsutsumi Abstract: Hsp90 chaperone function requires traversal of a nucleotide-dependent conformational cycle, but the slow and variable rate of Hsp90-mediated ATP hydrolysis is difficult to envision as a determinant of conformational change. A recent study solves this dilemma by showing that Hsp90 samples multiple conformational states in the absence of nucleotides, which serve to influence, but not direct, the cycle. The conformational program of Hsp90 is conserved from bacteria to humans, although the population dynamics are species specific. Author Affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA

Published
2009

33. Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90

Author

Kang, Byoung Heon, Plescia, Janet, Song, Ho Young, Meli, Massimiliano, Colombo, Giorgio, Beebe, Kristin, Scroggins, Bradley, Neckers, Len, and Altieri, Dario C.

Subjects
Antimitotic agents -- Physiological aspects, Antimitotic agents -- Genetic aspects, Antimitotic agents -- Research, Antineoplastic agents -- Physiological aspects, Antineoplastic agents -- Genetic aspects, Antineoplastic agents -- Research, Cellular signal transduction -- Health aspects, Heat shock proteins -- Physiological aspects, Heat shock proteins -- Health aspects
Abstract

Although therapeutically targeting a single signaling pathway that drives tumor development and/or progression has been effective for a number of cancers, in many cases this approach has not been successful. Targeting networks of signaling pathways, instead of isolated pathways, may overcome this problem, which is probably due to the extreme heterogeneity of human tumors. However, the possibility that such networks may be spatially arranged in specialized subcellular compartments is not often considered in pathway-oriented drug discovery and may influence the design of new agents. Hsp90 is a chaperone protein that controls the folding of proteins in multiple signaling networks that drive tumor development and progression. Here, we report the synthesis and properties of Gamitrinibs, a class of small molecules designed to selectively target Hsp90 in human tumor mitochondria. Gamitrinibs were shown to accumulate in the mitochondria of human tumor cell lines and to inhibit Hsp90 activity by acting as ATPase antagonists. Unlike Hsp90 antagonists not targeted to mitochondria, Gamitrinibs exhibited a "mitochondriotoxic" mechanism of action, causing rapid tumor cell death and inhibiting the growth of xenografted human tumor cell lines in mice. Importantly, Gamitrinibs were not toxic to normal cells or tissues and did not affect Hsp90 homeostasis in cellular compartments other than mitochondria. Therefore, combinatorial drug design, whereby inhibitors of signaling networks are targeted to specific subcellular compartments, may generate effective anticancer drugs with novel mechanisms of action., Introduction Backed by an unprecedented knowledge of cancer genes (1), it is now possible to disable signaling mechanisms of tumor cells without affecting normal tissues using targeted therapy (2), (3). [...]

Published
2009

34. The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors.

Author

Joshi, Abhinav, Ito, Takeshi, Picard, Didier, and Neckers, Len

Subjects
METABOLIC regulation, HEAT shock proteins, STRUCTURAL dynamics, MITOCHONDRIA, MOLECULAR chaperones, GLYCOLYSIS, HOMEOSTASIS, CYTOPROTECTION
Abstract

The HSP90 paralog TRAP1 was discovered more than 20 years ago; yet, a detailed understanding of the function of this mitochondrial molecular chaperone remains elusive. The dispensable nature of TRAP1 in vitro and in vivo further complicates an understanding of its role in mitochondrial biology. TRAP1 is more homologous to the bacterial HSP90, HtpG, than to eukaryotic HSP90. Lacking co-chaperones, the unique structural features of TRAP1 likely regulate its temperature-sensitive ATPase activity and shed light on the alternative mechanisms driving the chaperone's nucleotide-dependent cycle in a defined environment whose physiological temperature approaches 50 °C. TRAP1 appears to be an important bioregulator of mitochondrial respiration, mediating the balance between oxidative phosphorylation and glycolysis, while at the same time promoting mitochondrial homeostasis and displaying cytoprotective activity. Inactivation/loss of TRAP1 has been observed in several neurodegenerative diseases while TRAP1 expression is reported to be elevated in multiple cancers and, as with HSP90, evidence of addiction to TRAP1 has been observed. In this review, we summarize what is currently known about this unique HSP90 paralog and why a better understanding of TRAP1 structure, function, and regulation is likely to enhance our understanding of the mechanistic basis of mitochondrial homeostasis. [ABSTRACT FROM AUTHOR]

Published
2022
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