Author: Sandra Minotti ; Heather D. Durham ; Jieun R. C. Cha ; Ruihong Chen ; Allan E. Rubenstein ; Miranda L. Tradewell ; Benoit J. Gentil ; Zahara M. Jaffer ; Kyle J. H. St. Louis

Heat shock proteins (HSPs) are attractive therapeutic targets for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), characterized by aberrant formation of protein aggregates. Although motor neurons have a high threshold for activation of HSP genes, HSP90 inhibitors are effective inducers. This study evaluated NXD30001, a novel, small molecule HSP90 inhibitor based on the radicicol backbone, for its ability to induce neuronal HSPs and for efficacy in an experimental model of ALS based on mutations in superoxide-dismutase 1 (SOD1). In motor neurons of dissociated murine spinal cord cultures, NXD30001-induced expression of HSP70/HSPA1 (iHSP70) and its co-chaperone HSP40/DNAJ through activation of HSF1 and exhibited a protective profile against SOD1(G93A) similar to geldanamycin, but with less toxicity. Treatment prevented protein aggregation, mitochondrial fragmentation, and motor neuron death, important features of mutant SOD1 toxicity, but did not effectively prevent aberrant intracellular Ca(2+) accumulation. NXD30001 distributed to brain and spinal cord of wild-type and SOD1(G93A) transgenic mice following intraperitoneal injection; however, unlike in culture, in vivo levels of SOD1 were not reduced. NXD30001-induced expression of iHSP70 in skeletal and cardiac muscle and, to a lesser extent, in kidney, but not in liver, spinal cord, or brain, with either single or repeated administration. NXD30001 is a very useful experimental tool in culture, but these data point to the complex nature of HSP gene regulation in vivo and the necessity for early evaluation of the efficacy of novel HSP inducers in target tissues in vivo.

15 Jul 2013·Clinical Cancer ResearchQ1 · MEDICINE

Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2

Q1 · MEDICINE

Article

Author: Vitte, Jeremie ; Jaffer, Zahara M. ; White, Cory H. ; Nelson, Stanley F. ; Eskin, Ascia ; Jessen, Walter J. ; Chareyre, Fabrice ; Rubenstein, Allan E. ; Niwa-Kawakita, Michiko ; Manent, Jan ; Chen, Ruihong ; Giovannini, Marco ; Tanaka, Karo

AbstractPurpose: The growth and survival of neurofibromatosis type 2 (NF2)–deficient cells are enhanced by the activation of multiple signaling pathways including ErbBs/IGF-1R/Met, PI3K/Akt, and Ras/Raf/Mek/Erk1/2. The chaperone protein HSP90 is essential for the stabilization of these signaling molecules. The aim of the study was to characterize the effect of HSP90 inhibition in various NF2-deficient models.Experimental Design: We tested efficacy of the small-molecule NXD30001, which has been shown to be a potent HSP90 inhibitor. The antiproliferative activity of NXD30001 was tested in NF2-deficient cell lines and in human primary schwannoma and meningioma cultures in vitro. The antitumor efficacy of HSP90 inhibition in vivo was verified in two allograft models and in one NF2 transgenic model. The underlying molecular alteration was further characterized by a global transcriptome approach.Results: NXD30001 induced degradation of client proteins in and suppressed proliferation of NF2-deficient cells. Differential expression analysis identified subsets of genes implicated in cell proliferation, cell survival, vascularization, and Schwann cell differentiation whose expression was altered by NXD30001 treatment. The results showed that NXD30001 in NF2-deficient schwannoma suppressed multiple pathways necessary for tumorigenesis.Conclusions: HSP90 inhibition showing significant antitumor activity against NF2-related tumor cells in vitro and in vivo represents a promising option for novel NF2 therapies. Clin Cancer Res; 19(14); 3856–70. ©2013 AACR.

01 Sep 2010·Molecular Cancer TherapeuticsQ2 · MEDICINE

The Novel Hsp90 Inhibitor NXD30001 Induces Tumor Regression in a Genetically Engineered Mouse Model of Glioblastoma Multiforme

Q2 · MEDICINE

Article

Author: Rubenstein, Allan E. ; Bronson, Roderick T. ; Jaffer, Zahara M. ; Chen, Ruihong ; Winssinger, Nicolas ; Woolfenden, Steve ; Charest, Al ; Zhu, Haihao ; Barluenga, Sofia

AbstractGlioblastoma multiforme (GBM) has an abysmal prognosis. We now know that the epidermal growth factor receptor (EGFR) signaling pathway and the loss of function of the tumor suppressor genes p16Ink4a/p19ARF and PTEN play a crucial role in GBM pathogenesis: initiating the early stages of tumor development, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy. We have recently shown that this genetic combination is sufficient to promote the development of GBM in adult mice. Therapeutic agents raised against single targets of the EGFR signaling pathway have proven rather inefficient in GBM therapy, showing the need for combinatorial therapeutic approaches. An effective strategy for concurrent disruption of multiple signaling pathways is via the inhibition of the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 inhibition leads to the degradation of so-called client proteins, many of which are key effectors of GBM pathogenesis. NXD30001 is a novel second generation Hsp90 inhibitor that shows improved pharmacokinetic parameters. Here we show that NXD30001 is a potent inhibitor of GBM cell growth in vitro consistent with its capacity to inhibit several key targets and regulators of GBM biology. We also show the efficacy of NXD30001 in vivo in an EGFR-driven genetically engineered mouse model of GBM. Our findings establish that the Hsp90 inhibitor NXD30001 is a therapeutically multivalent molecule, whose actions strike GBM at the core of its drivers of tumorigenesis and represent a compelling rationale for its use in GBM treatment. Mol Cancer Ther; 9(9); 2618–26. ©2010 AACR.

100 Deals associated with NXD-30001

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma	Preclinical	US	Nexgenix Pharmaceuticals LLC	08 Sep 2010
Glioblastoma	Preclinical	US	Tufts Medical Center, Inc.	08 Sep 2010

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