Universitéde Strasbourg

Centre National De La Recherche Scientifique

The Scripps Research Institute

Nexgenix Pharmaceuticals, Inc.

Centre National De La Recherche Scientifique-cnrs

Université Louis Pasteur De Strasbourg

Le Centre National De La Recherche Scientifique

Karplus, Martin

Winssinger, Nicolas

Barluenga, Sofia

Martin Karplus

Nicolas Winssinger

Sofia Barluenga

Kyriacos Costa Nicolaou

Dionisios Vourloumis

Yun He

Sacha Ninkovic

Frank Roschangar

Hans Vallberg

Zhen Yang

Francisco Sarabia

Joaquin Pastor

Nigel Paul King

M Ray Finlay

Maurice Raymond Verschoyle Finlay

Tianhu Li

Jin-Chen Yu

Ruihong Chen

Allan E Rubenstein

N Paul King

Jin-You Xu

Jeff Pfefferkorn

Takashi Ohshima

Sanghee Kim

Seijiro Hosokawa

Floris VanDelft

John C Chabala

James Heck

Allan Rubenstein

Disclosed are macrocyclic compounds of formulae I, I', II, II&#x2032;, III, III&#x2032;, IV, and V, which are analogs of the pochonin resorcylic acid lactones, pharmaceutical compositions comprising the compounds, and methods and uses comprising the compounds for the treatment of diseases mediated by kinases and Heat Shock Protein 90 HSP90.

Synthesis of resorcylic acid lactones useful as therapeutic agents

A method for identifying one or several molecular structure(s) having a high-affinity for a target of interest, the molecular structure(s) each including one nucleotide chain onto which is hybridized at least one PNA-encoded molecule.

Method of preparing an adduct

Disclosed are novel analogues of the natural product radicicol A of formulae I, .Ia, pi, Ha, lib and HI, pharmaceutical compositions comprising the compounds. The compounds of the invention are kinase and phosphatase inhibitors and find utility in the treatment or prevention of kinase and phosphatase-mediated disorders. Also provided are uses and methods for the treatment or prevention of kinase- and phosphatase-mediated disorders and synthetic processes for the preparation of the compounds. 

Compositions and methods comprising analogues of radicicol A

Disclosed are macrocyclic compounds of formulae I-V, which are analogs of the pochonin resorcylic acid lactones, and processes for the preparation of the compounds. The compounds disclosed are useful as inhibitors of kinases and Heat Shock Protein 90 (HSP 90). Also disclosed are pharmaceutical compositions comprising an effective kinase-inhibiting amount or an effective HSP90-inhibiting amount of the compounds and methods for the treatment of disorders that are mediated by kinases and HSP90.

Macrocyclic compounds useful as inhibitors of kinases and HSP90

The present invention provides compounds of formulae Ia, Ia', IIa, IIa&#x2032;, IIIa, IIIa&#x2032;, IVa, or Va and the therapeutic use thereof. The present invention also includes methods of treating NF2-deficient or NF1-deficient cells or neurodegenerative diseases with radicicol or its derivatives, such as one or more compounds of formula I, II, III, IV, V, Ia, Ia&#x2032;, IIa, IIa&#x2032;, IIIa, IIIa&#x2032;, IVa, or Va. Furthermore, the present invention is directed to methods of inhibiting the growth of NF2-deficient or NF1-deficient tumors. The methods comprise contacting NF2-deficient or NF1-deficient tumor cells with radicicol or its derivatives, such as one or more compounds of formula I, II, III, IV, V, Ia, Ia&#x2032;, IIa, IIa&#x2032;, IIIa, IIIa&#x2032;, IVa, or Va. The present invention is also directed to the combinational use of radicicol or its derivatives, such as one or more compounds of formula I, II, III, IV, V, Ia, Ia&#x2032;, IIa, IIa&#x2032;, IIIa, IIIa&#x2032;, IVa, or Va with at least one additional active agent, such as one or more HSP90 inhibitors.

Treatment of neurofibromatosis with radicicol and its derivatives

Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancers agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubulin assembly. The analogs of epothilone are novel. Several of the analogs are demonstrated to have a superior cytotoxic activity as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

Epothilone analogs

Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancers agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubule assembly. The analogs of epothilone are novel. Several of the analogs are demonstrated to have a superior cytotoxic activity as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancer agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubulin assembly. The analogs of epothilone are novel. Several of the anlogs are demonstrated to have a superior cytotoxic activities as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

Sarcodictyin A and B, eleutherobin, and bioactive analogs thereof synthesized using solid phase and solution phase chemistries. The synthetic method employs an attachment of common precursors, e.g., compounds 1880 or 200, on a solid support for generating conjugates 230 and 240, followed by standard chemical manipulations. A combinatorial library of sarcodictyins and eletherobin analogs was constructed with modified C-8 ester, C-15 ester and C-4 ketal functionalities and was screened for activity with respect to tubulin polymerization and cytotoxic activity against tumor cells, including Taxol-resistant lines. Compounds 600, 610, 630, 660-700, 730, 760, 850, and 920 were identified to be of equal or superior biological activities as compared to their corresponding natural product.

Analogs of sarcodictyin and eleutherobin

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Strasbourg, France

Nicolas Winssinger