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Breast Cancer Research | 2008

NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models

Michael Rugaard Jensen; Joseph Schoepfer; Thomas Radimerski; Andrew Massey; Chantale T. Guy; Josef Brueggen; Cornelia Quadt; Alan J. Buckler; Robert Cozens; Martin J. Drysdale; Carlos Garcia-Echeverria; Patrick Chène

IntroductionHeat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the post-translational folding of a large number of client proteins, many of which play essential roles in tumorigenesis. HSP90 has emerged in recent years as a promising new target for anticancer therapies.MethodsThe concentrations of the HSP90 inhibitor NVP-AUY922 required to reduce cell numbers by 50% (GI50 values) were established in a panel of breast cancer cell lines and patient-derived human breast tumors. To investigate the properties of the compound in vivo, the pharmacokinetic profile, antitumor effect, and dose regimen were established in a BT-474 breast cancer xenograft model. The effect on HSP90-p23 complexes, client protein degradation, and heat shock response was investigated in cell culture and breast cancer xenografts by immunohistochemistry, Western blot analysis, and immunoprecipitation.ResultsWe show that the novel small molecule HSP90 inhibitor NVP-AUY922 potently inhibits the proliferation of human breast cancer cell lines with GI50 values in the range of 3 to 126 nM. NVP-AUY922 induced proliferative inhibition concurrent with HSP70 upregulation and client protein depletion – hallmarks of HSP90 inhibition. Intravenous acute administration of NVP-AUY922 to athymic mice (30 mg/kg) bearing subcutaneous BT-474 breast tumors resulted in drug levels in excess of 1,000 times the cellular GI50 value for about 2 days. Significant growth inhibition and good tolerability were observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers, including HSP90-p23 dissociation, decreases in ERBB2 and P-AKT, and increased HSP70 protein levels.ConclusionNVP-AUY922 is a potent small molecule HSP90 inhibitor showing significant activity against breast cancer cells in cellular and in vivo settings. On the basis of its mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, the compound recently has entered clinical phase I breast cancer trials.


Proceedings of the National Academy of Sciences of the United States of America | 2013

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

Adrian Britschgi; Anke Bill; Heike Brinkhaus; Christopher Rothwell; Ieuan Clay; Stephan Duss; Michael Rebhan; Pichai Raman; Chantale T. Guy; Kristie Wetzel; Elizabeth George; M. Oana Popa; Sarah Lilley; Hedaythul Choudhury; Martin Gosling; Louis Wang; Stephanie Fitzgerald; Jason Borawski; Jonathan Baffoe; Mark Labow; L. Alex Gaither; Mohamed Bentires-Alj

The calcium-activated chloride channel anoctamin 1 (ANO1) is located within the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human cancer, but its functional role in tumorigenesis has remained unclear. The 11q13 region is amplified in ∼15% of breast cancers. Whether ANO1 is amplified in breast tumors, the extent to which gene amplification contributes to ANO1 overexpression, and whether overexpression of ANO1 is important for tumor maintenance have remained unknown. We have found that ANO1 is amplified and highly expressed in breast cancer cell lines and primary tumors. Amplification of ANO1 correlated with disease grade and poor prognosis. Knockdown of ANO1 in ANO1-amplified breast cancer cell lines and other cancers bearing 11q13 amplification inhibited proliferation, induced apoptosis, and reduced tumor growth in established cancer xenografts. Moreover, ANO1 chloride channel activity was important for cell viability. Mechanistically, ANO1 knockdown or pharmacological inhibition of its chloride-channel activity reduced EGF receptor (EGFR) and calmodulin-dependent protein kinase II (CAMKII) signaling, which subsequently attenuated AKT, v-src sarcoma viral oncogene homolog (SRC), and extracellular signal-regulated kinase (ERK) activation in vitro and in vivo. Our results highlight the involvement of the ANO1 chloride channel in tumor progression and provide insights into oncogenic signaling in human cancers with 11q13 amplification, thereby establishing ANO1 as a promising target for therapy in these highly prevalent tumor types.


Journal of Biomolecular Screening | 2013

Identification of Cardiac Glycoside Molecules as Inhibitors of c-Myc IRES-Mediated Translation

Marie-Cecile Didiot; Jeffrey Hewett; Thibault Varin; Felix Freuler; Douglas W. Selinger; Hanspeter Nick; Juergen Reinhardt; Alan J. Buckler; Vic E. Myer; Ansgar Schuffenhauer; Chantale T. Guy; Christian N. Parker

Translation initiation is a fine-tuned process that plays a critical role in tumorigenesis. The use of small molecules that modulate mRNA translation provides tool compounds to explore the mechanism of translational initiation and to further validate protein synthesis as a potential pharmaceutical target for cancer therapeutics. This report describes the development and use of a click beetle, dual luciferase cell-based assay multiplexed with a measure of compound toxicity using resazurin to evaluate the differential effect of natural products on cap-dependent or internal ribosome entry site (IRES)–mediated translation initiation and cell viability. This screen identified a series of cardiac glycosides as inhibitors of IRES-mediated translation using, in particular, the oncogene mRNA c-Myc IRES. Treatment of c-Myc–dependent cancer cells with these compounds showed a decrease in c-Myc protein associated with a significant modulation of cell viability. These findings suggest that inhibition of IRES-mediated translation initiation may be a strategy to inhibit c-Myc–driven tumorigenesis.


Scientific Reports | 2017

Identification of a novel NAMPT inhibitor by CRISPR/Cas9 chemogenomic profiling in mammalian cells

David Estoppey; Jeffrey Hewett; Chantale T. Guy; Edmund Harrington; Jason R Thomas; Markus Schirle; Rachel Cuttat; Annick Waldt; Bertran Gerrits; Zinger Yang; Sven Schuierer; Xuewen Pan; Kevin Xie; Walter Carbone; Judith Knehr; Alicia Lindeman; Carsten Russ; Elizabeth Frias; Gregory R. Hoffman; Malini Varadarajan; Nadire Ramadan; John S. Reece-Hoyes; Qiong Wang; Xin Chen; Gregory McAllister; Guglielmo Roma; Tewis Bouwmeester; Dominic Hoepfner

Chemogenomic profiling is a powerful and unbiased approach to elucidate pharmacological targets and the mechanism of bioactive compounds. Until recently, genome-wide, high-resolution experiments of this nature have been limited to fungal systems due to lack of mammalian genome-wide deletion collections. With the example of a novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, we demonstrate that the CRISPR/Cas9 system enables the generation of transient homo- and heterozygous deletion libraries and allows for the identification of efficacy targets and pathways mediating hypersensitivity and resistance relevant to the compound mechanism of action.


Bioorganic & Medicinal Chemistry Letters | 2017

Structure based design of Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors from a phenotypic screen

Daniel Steven Palacios; Erik Meredith; Toshio Kawanami; Christopher Michael Adams; Xin Chen; Veronique Darsigny; Erin Geno; Mark G. Palermo; Daniel Baird; Geoffrey Boynton; Scott A. Busby; Elizabeth George; Chantale T. Guy; Jeffrey Hewett; Laryssa Tierney; Sachin Thigale; Wilhelm Weihofen; Louis Wang; Nicole White; Ming Yin; Upendra A. Argikar

Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo.


Cancer Research | 2013

Abstract LB-205: The calcium activated chloride channel ANO1 promotes breast cancer progression by activating EGFR- and CAMK-signaling.

Adrian Britschgi; Anke Bill; Heike Brinkhaus; Christopher Rothwell; Ieuan Clay; Stephan Duss; Michael Rebhan; Pichai Raman; Chantale T. Guy; Kristie Wetzel; Elizabeth George; M. Oana Popa; Sarah Lilley; Hedaythul Choudhury; Martin Gosling; Louis Wang; Stephanie Fitzgerald; Jason Borawski; Jonathan Baffoe; Mark Labow; L. Alex Gaither; Mohamed Bentires-Alj

Genomic alterations are the underlining cause of many human cancers: Amplified and overexpressed genes can drive neoplastic transformation and become essential survival factors for cancer cells. Thus, they represent promising targets for anti-cancer therapies and their identification and validation is of paramount importance. In a search for novel survival factors contributing to breast cancer oncogenesis, we performed genomic fine mapping of the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human neoplasia, in a large dataset of breast cancer patients. Remarkably, we found ANO1, a calcium-activated chloride channel, to be located within the summit of the most frequently and highly amplified genomic region. Furthermore, amplification of ANO1 correlates with its overexpression and elevated protein levels and is a negative predictor for overall survival in breast cancer patients. Next, we examined how ANO1 contributes to cancer cell survival and proliferation. We found that inhibition of ANO1 expression or function reduced cancer cell viability and colony formation, and triggered apoptosis in 11q13 amplified breast cancer, HNSCC and ESCC. Furthermore, expression of ANO1 in non-transformed mammary cells increased cell viability and established a novel addiction to ANO1 biochemical activity. We next applied inducible shRNAs against ANO1 in vivo to assess the effect of ANO1 inhibition on the maintenance of established tumors. We found in four different 11q13-amplified tumor models that knockdown of ANO1 reduced tumor growth, indicating an important role for ANO1 not only in oncogenesis, but also in tumor maintenance of 11q13 amplified cancers. To explore the mechanism by which inhibition of ANO1 contributes to cancer cell viability and tumor growth, we performed antibody arrays to measure the activity of major oncogenic signaling pathways after knockdown of ANO1. Upon depletion of ANO1, activation of EGFR and several survival signaling pathways (AKT-, SRC- and ERK1/2 pathways) were reduced in different models of human cancer. Subsequent experiments showed that ANO1 modulates both EGFR- and Ca2+/calmodulin-dependent protein kinase (CAMK) signaling in breast cancer and HNSCC cells. Consistently, activation of EGFR- and CAMK correlated with the expression of ANO1 in human primary breast tumor samples. Lastly, we found that only the simultaneous stimulation of EGFR- and CAMK-signaling pathways rescued the effect of the ANO1-inhibition. In summary, our study establishes ANO1 as a key tumor-promoting factor in 11q13-amplified breast and other malignancies. Our results highlight the importance of chloride channels in cancer and provide the first detailed mechanistic insight into the activity of ANO1 in tumorigenesis. Most importantly, our findings open up new opportunities for therapeutic intervention in several prevalent cancers. Citation Format: Adrian Britschgi, Anke Bill, Heike Brinkhaus, Christopher Rothwell, Ieuan Clay, Stephan Duss, Michael Rebhan, Pichai Raman, Chantale Guy, Kristie Wetzel, Elizabeth George, M. Oana Popa, Sarah Lilley, Hedaythul Choudhury, Martin Gosling, Louis Wang, Stephanie Fitzgerald, Jason Borawski, Jonathan Baffoe, Mark Labow, L. Alex Gaither, Mohamed Bentires-Alj. The calcium activated chloride channel ANO1 promotes breast cancer progression by activating EGFR- and CAMK-signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-205. doi:10.1158/1538-7445.AM2013-LB-205


Archive | 2010

Diagnostic BioMarkers for Fibrotic Disorders

Alan J. Buckler; Chao-Min Chen; Chantale T. Guy; Jeffrey Hewett


Cancer Research | 2011

Abstract 2605: Identification and development of NVP-HSP990, a potent and orally active Hsp90 inhibitor for cancer treatment

Zhenhai Gao; Timothy Machajewski; Daniel Menezes; Michael Rugaard Jensen; Karen Yu; Chantale T. Guy


Archive | 2010

Biomarkers of tumor pharmacodynamic response

Michaela Bowden; Alan J. Buckler; Chantale T. Guy


Archive | 2010

METHODS OF MODULATING FIBROSIS USING BONE MORPHOGENETIC PROTEIN-9 (BMP-9) MODULATORS

Alan J. Buckler; Chao-Min Chen; Chantale T. Guy; Jeffrey Hewett

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