Tel Aviv, Israel
Tel Aviv, Israel

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El-Ami T.,Hebrew University of Jerusalem | Moll L.,Hebrew University of Jerusalem | Carvalhal Marques F.,Hebrew University of Jerusalem | Carvalhal Marques F.,University of Coimbra | And 3 more authors.
Aging Cell | Year: 2014

Aging manipulation is an emerging strategy aimed to postpone the manifestation of late-onset neurodegenerative disorders such as Alzheimer's (AD) and Huntington's diseases (HD) and to slow their progression once emerged. Reducing the activity of the insulin/IGF signaling cascade (IIS), a prominent aging-regulating pathway, protects worms from proteotoxicity of various aggregative proteins, including the AD-associated peptide, Aβ- and the HD-linked peptide, polyQ40. Similarly, IGF1 signaling reduction protects mice from AD-like disease. These discoveries suggest that IIS inhibitors can serve as new drugs for the treatment of neurodegenerative maladies including AD and HD. Here, we report that NT219, a novel IIS inhibitor, mediates a long-lasting, highly efficient inhibition of this signaling cascade by a dual mechanism; it reduces the autophosphorylation of the IGF1 receptor and directs the insulin receptor substrates 1 and 2 (IRS 1/2) for degradation. NT219 treatment promotes stress resistance and protects nematodes from AD- and HD-associated proteotoxicity without affecting lifespan. Our discoveries strengthen the theme that IIS inhibition has a therapeutic potential as a cure for neurodegenerative maladies and point at NT219 as a promising compound for the treatment of these disorders through a selective manipulation of aging. © 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Reuveni H.,NovoTyr Therapeutics Ltd. | Reuveni H.,Hebrew University of Jerusalem | Flashner-Abramson E.,Hebrew University of Jerusalem | Steiner L.,NovoTyr Therapeutics Ltd. | And 8 more authors.
Cancer Research | Year: 2013

Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and antiapoptotic signaling from insulinlike growth factor 1 receptor (IGF-IR), insulin receptor (IR), and other oncoproteins. IRS1 plays a central role in cancer cell proliferation, its expression is increased in many human malignancies, and its upregulation mediates resistance to anticancer drugs. IRS2 is associated with cancer cell motility and metastasis. Currently, there are no anticancer agents that target IRS1/2. We present new IGF-IR/IRS-targeted agents (NT compounds) that promote inhibitory Ser-phosphorylation and degradation of IRS1 and IRS2. Elimination of IRS1/2 results in long-term inhibition of IRS1/2-mediated signaling. The therapeutic significance of this inhibition in cancer cells was shown while unraveling a novel mechanism of resistance to B-RAFV600E/K inhibitors. We found that IRS1 is upregulated in PLX4032-resistant melanoma cells and in cell lines derived from patients whose tumors developed PLX4032 resistance. In both settings, NT compounds led to the elimination of IRS proteins and evoked cell death. Treatment with NT compounds in vivo significantly inhibited the growth of PLX4032-resistant tumors and displayed potent antitumor effects in ovarian and prostate cancers. Our findings offer preclinical proof-of-concept for IRS1/2 inhibitors as cancer therapeutics including PLX4032-resistant melanoma. By the elimination of IRS proteins, such agents should prevent acquisition of resistance to mutated-B-RAF inhibitors and possibly restore drug sensitivity in resistant tumors. © 2013 AACR.

The present invention provides compounds of formula (1) acting as protein kinase (PK) and receptor kinase (RK) signaling modulators. The invention further provides methods of their preparation, pharmaceutical compositions including such compounds, and methods of using these compounds and compositions, especially as anti-cancer agents for preventions and treatments of PK- and RK-related disorders, in particular cancer. (I) wherein A is H or CN; Z is S, SO or S0_(2); X^(1), X^(2), X^(3), X^(4), X^(5), Y^(1 )and Y^(2 )are each independently selected from H, halogen, alkyl, haloalkyl and OR^(1); and Y^(3 )and Y^(4 )are each OR^(1), wherein each R^(1 )is independently H, C_(1)-C_(4 )alkyl, acyl, (CH_(2)CH_(2)0)_(n )wherein n is an integer of 1 to 20, or a functional group that gives rise to hydroxyl upon hydrolysis.

Novotyr Therapeutics Ltd. | Date: 2011-11-10

The present invention provides new tyrphostin derivatives acting as protein tyrosine kinase (PTK) inhibitors and receptor tyrosine kinase (RTK) inhibitors, and/or which directly or indirectly affect proteins in the PTK-mediated signal transduction pathway, methods of their preparation, pharmaceutical compositions including such compounds, and methods of using these compounds and compositions, especially as chemotherapeutic agents for preventions and treatments of PTK and RTK related disorders such as metabolic, fibrotic, and cell proliferative disorders, in particular psoriasis and cancer.

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