Abstract: The present invention provides compositions and methods for treating proliferative disorders using combination therapies of lometrexol and other therapeutically active agents. The methods include administration of lometrexol with one or more therapeutically active agents where lometrexol and the therapeutically active agent(s) are delivered in a single composition, where they are administered in separate compositions in a simultaneous manner, where lometrexol is administered first, followed by the therapeutically active agent(s), as well as where the therapeutically active agent(s) is delivered first, followed by lometrexol. In preferred embodiments, the therapeutically active agent(s) has antiproliferative properties.

Abstract: The present invention provides compounds, compositions and methods for the inhibition or treatment of conditions or disorders modulated by the STAT transcription factors, particularly STAT4 and STAT6. Additionally, the compounds are useful for the diagnosis of conditions dependent on STAT signaling.

Abstract: The present invention provides methods, reagents, and kits for diagnosing and treating cancer in a mammal, e.g., a human. This invention is based upon the discovery that Pellino 1 or 2 is overexpressed and/or amplified in cancer. Methods to detect cancer or a propensity to develop cancer, to monitor the efficacy of a cancer treatment, and to treat cancer, by inhibiting the expression and/or activity of Pellino 1 or 2 in a cancer cell are included.

Abstract: This invention provides methods and compositions that are useful for modulating cholesterol levels in a cell, and for identifying compounds that can tested for ability to modulate cholesterol levels in mammals. In vitro assays for prescreening to identify candidate therapeutic agents for modulation of cholesterol metabolism are provided. These methods involve analyzing the effect of a test compound on the binding of FXR to a ligand for FXR. Such ligands include, for example, bile acids, coactivators, and corepressors. The methods and compositions involve modulating FXR-mediated expression of genes involved in cholesterol metabolism.

Abstract: Compounds, compositions and methods are provided that are useful in the treatment and prevention of certain viral infections and associated diseases. In particular, the compounds of the invention inhibit the activity of a viral RNA polymerase. The subject methods are particularly useful in the treatment of diseases causes by hepatitis C virus infection.

Abstract: The invention provides methods and compositions relating to novel pentafluorophenylsulfonamide derivatives and analogs and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly atherosclerosis and hypercholesterolemia, or as lead compounds for the development of such agents.

Abstract: The present invention provides compounds, pharmaceutical compositions and methods that are useful in modulating the farnesoid X receptor (FXR). As FXR is involved in negatively controlling the expression level of cholesterol 7&agr;-hydroxylase (cyp7a), the rate-limiting enzyme involved in the oxidative metabolism of cholesterol into bile acids, the compounds described herein find utility in treating diseases associated with abnormally high or low cholesterol levels. In certain aspects, the FXR modulators (e.g., antagonists) described herein block the negative feed-back downregulation of cyp7a expression produced by certain cholic acids, the endogenous ligands for FXR. Moreover, as FXR forms heterodimers with the retinoid X receptor (RXR) in some cell types, modulation of the level of FXR activity in cells has a wide range of effects on a variety of biological processes which are mediated by RXR or other RXR-interacting proteins such as PPAR&ggr; and PPAR&agr;.

Abstract: The invention provides methods and compositions relating to Suppressor of Death Domain (SODD) proteins which regulate cellular signal transduction and transcriptional activation, and related nucleic acids. The polypeptides may be produced recombinantly from transformed host cells from the disclosed SODD encoding nucleic acids or purified from human cells. The invention provides isolated SODD hybridization probes and primers capable of specifically hybridizing with the disclosed SODD genes, SODD-specific binding agents such as specific antibodies, and methods of making and using the subject compositions in diagnosis, therapy and in the biopharmaceutical industry.

Abstract: The invention provides methods and compositions for screening for pharmacological agents which regulate satiety, fat metabolism and/or the type II diabetes mellitus in mammals, and in particular, agents active at regulating the level of ob gene expression. An exemplary assay involves (a) contacting a mammalian adipocyte comprising a mutant of a native ob allele encoding a reporter of ob gene expression, wherein the expression of the reporter is under the control of the gene expression regulatory sequences of the native ob allele, with a candidate agent under conditions whereby but for the presence of the agent, the reporter is expressed at a first expression level; and, (b) measuring the expression of the reporter to obtain a second expression level, wherein a difference between the first and second expression levels indicates that the candidate agent modulates ob gene expression.

Abstract: Derivatives of known tubulin-binding compounds are provided in which a (poly)fluorobenzene, a fluoropyridine, or a fluoronitrobenzene moiety is incorporated or added to the structure. These derivatives can be used as antimitotic agents and can be considered covalent modifiers of tubulin. The strategy developed for each of the compounds is to i) append a fluorinated electrophile (e.g., pentafluorophenylsulfonamido, 2-fluoropyridyl, or 3,5-dinitro-4-fluorophenyl) to an existing functional group in a natural product, ii) replace an aromatic ring in a natural product with a fluorinated electrophile, or iii) attach a fluorinated electrophile to an open valence in a portion of the molecule that will not interfere with recognition and binding to the tubulin site. Derivatives are provided based on colchicine, steganacin, podophyllotoxin, nocodazole, combretastatin, curacin A, vinblastine, vincristine, dolastatin, 2-methoxyestradiol, dihydroxy-pentamethoxyflavanone and others.

Abstract: This invention relates to monoclonal antibodies that recognize modified &bgr;-tubulin isotypes, methods of using such antibodies to detect modified &bgr;-tubulin isotypes, methods of using such antibodies to monitor &bgr;-tubulin modifying agents administered to a patient, methods of using such antibodies to isolate modified &bgr;-tubulin, and methods of detecting the anti-modified &bgr;-tubulin antibodies.

Abstract: Compounds, compositions and methods that are useful in the treatment of immunoregulatory conditions and disorders are provided herein. In particular, the invention provides compounds which modulate the function of a Signal Transducer and Activator of Transcription (STAT) protein. The compounds are represented by the general formula: wherein Y, Ar, X, A2, A1, R1 and R2 are defined herein. The compounds are useful to treat, for example, allergic and inflammatory conditions and disorders.

Abstract: The invention provides compounds, compositions and methods relating to novel arylsulfonanilide derivatives and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly cancer, psoriasis, vascular restenosis, infections, atherosclerosis and hypercholesterolemia, or as lead compounds for the development of such agents.

Abstract: The invention provides methods and compositions relating to Suppressor of Death Domain (SODD) proteins which regulate cellular signal transduction and transcriptional activation, and related nucleic acids. The polypeptides may be produced recombinantly from transformed host cells from the disclosed SODD encoding nucleic acids or purified from human cells. The invention provides isolated SODD hybridization probes and primers capable of specifically hybridizing with the disclosed SODD genes, SODD-specific binding agents such as specific antibodies, and methods of making and using the subject compositions in diagnosis, therapy and in the biopharmaceutical industry.

Abstract: Salts of pyrimidine derivatives are provided having the formula: wherein R represents hydrogen, methyl or ethyl; Z represents a substituted or unsubstituted 1-piperidinyl, a substituted or unsubstituted 4-morpholinyl, or a substituted or unsubstituted 1-pyrrolidinyl; and Ar represents a substituted or unsubstituted phenyl or a substituted or unsubstituted naphthyl. These salts are particularly useful as antiviral agents (e.g., to treat CMV infections).

Abstract: The invention provides compounds, compositions and methods relating to novel electrophilic aromatic derivatives and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly cancer, psoriasis, vascular restenosis, infections, atherosclerosis and hypercholesterolemia, or as lead compounds for the development of such agents.

Abstract: Certain six-membered aromatic and heteroaromatic-dioxobutyric acid derivatives are described as inhibitors of HIV integrase and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

Abstract: The invention provides methods and compositions for diagnosing and treating tumors. In particular embodiments, the invention provides methods for characterizing tumors for SODD gene copy number and/or expression and for using this diagnosis in guiding treatment options. Accordingly, the invention provides methods for biasing therapeutic options by (a) contacting a biopsy of a tumor with an agent which specifically binds a SODD gene or SODD gene product thereof; (b) measuring specific binding of the agent to the SODD gene or gene product to determine an amount of the SODD gene or gene product present in the biopsy; and (c) biasing therapeutic options for treating the tumor based on the amount of the SODD gene or gene product present in the biopsy.

Abstract: T2K kinase activity is detected by forming a mixture of a T2K kinase and a substrate; incubating the mixture under conditions whereby the kinase phosphorylates the substrate at a first rate; and detecting the first rate as an indication of the kinase activity. The substrate comprises SX1X2X3SX4 (SEQ ID NO:1) wherein X1 and X4 are aliphatic residues and both of the S residues are targets of the kinase, and especially, IKK&agr; or IKK&bgr;. In another embodiment, the mixture substrate comprises a particular IL-1 or TNF signaling cascade component. The mixture may be used to screen for agents which modulate the activity of the kinase, e.g. as an immuno-chemiluminescent assay.

Abstract: Combination therapies are provided for the treatment of proliferative disorders which use a pentafluorobenzenesulfonamide of formula I and an antineoplastic platinum coordination complex such as cisplatin.