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Paris, France

Qin S.,DuPont Company | Ni M.,DuPont Company | Wang X.,DuPont Company | Maurier-Mahe F.,ExonHit Therapeutics | And 2 more authors.
Experimental Eye Research | Year: 2011

Dying cells release pro-inflammatory molecules, functioning as cytokines to trigger cell/tissue inflammation that is relevant to disease pathology. Heat-shock protein 90 (HSP90) is believed to act as a danger signal for tissue damage once released extracellularly. Potential roles of HSP90 were explored in retinal pigment epithelial (RPE) inflammatory responses to necrosis. Cellular extracts can trigger ARPE-19 cell inflammatory responses, producing cytokines that lead to an increase in ARPE-19 cell monolayer permeability. Addition of recombinant HSP90β mimics the induction of chemokines IL-8 and MCP-1 in cultured RPE cells, suggesting that released HSP90 can incite RPE cellsterile inflammatory responses. Consistent with this, classical HSP90 inhibitors were shown to substantially reduce necrosis-induced cytokine production and permeability increases in ARPE-19 cells. Moreover, a cell-impermeable inhibitor, 17-N, N-dimethylaminoethylamino-17-demethoxy-geldanamycin-N-oxide, also efficiently inhibited necrosis-induced cytokine production and TNF-α/IL-1β-induced increase in ARPE-19 cell permeability invitro and endotoxin-induced development of uveitis invivo, suggesting that HSP90 can contribute to necrosis-induced RPE inflammatory responses. Collectively, our data identify HSP90 as a pro-inflammatory molecule in RPE cell sterile inflammatory responses. © 2011 Elsevier Ltd. Source

ExonHit Therapeutics | Date: 2012-03-28

The present invention relates to the fields of biology, genetics and medicine. In particular it concerns new methods for the detection, characterisation and/or treatment (or management) of neurodegenerative diseases, particularly amyotrophic lateral sclerosis. The invention equally concerns methods for identifying or screening compounds active in these diseases. The invention further concerns the compounds, genes, cells, plasmids or compositions useful for implementing the hereinabove methods. In particular, the invention describes the role of PDE4B in these diseases and its use as a therapeutic, diagnostic or experimental target.

ExonHit Therapeutics | Date: 2010-07-09

The present invention relates generally to the fields of genetics, biochemistry, medicinal chemistry and medicine. The present invention more particularly discloses the identification of a human gene variant involved in neuropathological conditions, and methods for the diagnosis, prevention and treatment of such diseases and related disorders, as well as for the screening of therapeutically active drugs. The present invention relates to catalytically active beta-secretase (Memapsin2, BACE) variants, and nucleic acids encoding them. The invention is useful in the identification of agents that inhibit the activity of a particular BACE isoform and thus agents and therapies affecting the genesis, development or progression of neuropathological conditions, including Alzheimers disease and dementia.

Compounds of Formulas 1 and 2 where the variables have the meaning disclosed in the specification, have analgesic and in some cases immunostimulant activity.

ExonHit Therapeutics and Allergan, Inc. | Date: 2012-02-17

The invention relates to compounds of the formula wherein R, R

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