Abstract: The present invention provides for a method of using BOC/CDO hedgehog antagonists to inhibit hedgehog signaling, as well as treating and diagnosing disorders relating to hedgehog signaling or overexpression of hedgehog, including cancer, cell proliferative disorders, and angiogenesis, neurological disorders, as well as other conditions affected by hedgehog signaling such as hair growth, neural stem cell differentiation, chondrogenesis and osteogenesis, lung surfactant production, formation of lamellated bodies in lung cells.

Abstract: The present invention relates to tyrosine kinase inhibitors that contain a zinc-binding moiety and their use in the treatment of tyrosine related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.

Abstract: Variants of hedgehog protein that contain N-terminal modifications are described that can block hedgehog function; thus allowing these variants to serve as functional antagonists. These peptides have a primary amino acid sequence lacking the ability to elicit a hedgehog-dependent response in C3H 10T1/2 cells but having the ability to bind to the hedgehog receptor, patched-1. Methods for producing such functional antagonists and methods of using the functional antagonists are also described.

Abstract: The instant application relates to deazapurines, thienopyrimidines and furopyrimidines with zinc-binding moiety based derivatives and their use in the treatment of phosphoinositide 3-kinase related diseases and disorders such as cancer. The instant application further relates to the the treatment of histone deacetylase related disorders and diseases related to both histone deacetylase and phosphoinositide 3-kinase.

Abstract: The present application is directed to compositions and methods for inhibiting angiogenesis and treating or preventing unwanted cell proliferation, including tumors, by inhibiting the hedgehog pathway, e.g., with an antagonist of the hedgehog pathway such as those disclosed herein.

Abstract: The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function comprising contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth, e.g., to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity.

Abstract: The present invention relates to quinazoline containing zinc-binding moiety based derivatives of formula I that have enhanced and unexpected properties as inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer.

Abstract: The present invention relates to HSP90 inhibitors containing fused amino pyridine core that are useful as inhibitors of HSP90 and their use in the treatment of HSP90 related diseases and disorders such as cancer, an autoimmune disease, or a neurodegenerative disease.

Abstract: The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function comprising contacting the cell with a hedgehog antagonist of formula (I) in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity.

Abstract: The emergence of mutations in tyrosine kinases following treatment of cancer patients with molecular-targeted therapy represents a major mechanism of acquired drug resistance. Here, we describe a mutation in the serpentine receptor, Smoothened (SMO), which results in resistance to a Hedgehog (Hh) pathway inhibitor in medulloblastoma. A single amino acid substitution in a conserved aspartic acid residue of SMO maintains Hh signaling, but results in the inability of the Hh pathway inhibitor, GDC-0449, to bind SMO and suppress the pathway. This mutation was not only acquired in a GDC-0449-resistant mouse model of medulloblastoma, but was identified in a Medulloblastoma patient following relapse on GDC-0449. The invention provides screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.

Abstract: The present application is directed to the discovery that hedgehog gene products, and signal transduction pathways involving hedgehog, are involved in maturation of T lymphocytes. The invention provides a method to promote T lymphocyte development using low dose Hedghog, and a method to inhibit T lymphocyte development using high dose Hedgehog. Certain aspects of the invention are directed to preparations of hedgehog polypeptides, agonists, antagonists, or other molecules which regulate patched or smoothened signalling, and their uses as immunomodulatory agents.

Abstract: The invention provides novel inhibitors of hedgehog signaling that are useful as a therapeutic agents for treating malignancies where the compounds have the general formula I: wherein A is a carbocycle or heterocycle; X is alkylene, NR4C(O), NR4C(S), NR4C(NH), NR4SO, NR4SO2, NR4C(O)NH, NR4C(S)NH, C(O)NR4, C(S)NR4, C(NH)NR4, NR4PO or NR4PO(OH) wherein R4 is H or alkyl; R1 is selected from the group consisting of alkyl, cycloalkyl, aryl or a heterocycle each of which is optionally substituted with hydroxy, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; R2 is halogen, hydroxy, alkyl, acyl or alkoxy each optionally substituted with hydroxy, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; R3 is halogen, hydroxy, alkyl, acyl or alkoxy each optionally substituted with hydroxy, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; m is 0-3; n is 0-3; and salts and solvates thereof.

Abstract: The present invention relates to substituted 2-indolinone containing zinc-binding moiety based derivatives that have enhanced or unique properties as inhibitors of protein tyrosine kinase (PTK) receptors and their use in the treatment of PTK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.

Abstract: The present invention makes available methods and reagents for modulating proliferation or differentiation in a cell or tissue comprising contacting the cell with a compound. In certain embodiments, the methods and reagents may be employed to correct or inhibit an aberrant or unwanted growth state, e.g., by antagonizing a normal patched pathway or agonizing smoothened or hedgehog activity.

Abstract: The present application is directed to the discovery that preparations of hedgehog polypeptides can be used to control the formation and/or maintenance of epithelial tissue.

Abstract: The present invention provides for a method of using BOC/CDO hedgehog antagonists to inhibit hedgehog signaling, as well as treating and diagnosing disorders relating to hedgehog signaling or overexpression of hedgehog, including cancer, cell proliferative disorders, and angiogenesis, neurological disorders, as well as other conditions affected by hedgehog signaling such as hair growth, neural stem cell differentiation, chondrogenesis and osteogenesis, lung surfactant production, formation of lamellated bodies in lung cells.

Abstract: The present application is directed to the discovery that hedgehog gene products, and signal transduction pathways involving hedgehog, are involved in maturation of T lymphocytes. The invention provides a method to promote T lymphocyte development using low dose Hedgehog, and a method to inhibit T lymphocyte development using high dose Hedgehog. Certain aspects of the invention are directed to preparations of hedgehog polypeptides, agonists, antagonists, or other molecules which regulate patched or smoothened signalling, and their uses as immunomodulatory agents.

Abstract: The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function comprising contacting the cell with a hedgehog antagonist of formula (I) in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity.

Abstract: The present invention makes available methods and reagents for modulating proliferation or differentiation in a cell or tissue comprising contacting the cell with a hedgehog agonist, such as the compounds depicted in FIGS. 32 and 33. In certain embodiments, the methods and reagents may be employed to correct or inhibit an aberrant or unwanted growth state, e.g., by antagonizing a normal ptc pathway or agonizing smoothened or hedgehog activity.

Abstract: The present invention relates to a composition comprising an inclusion complex of a cyclodextrin and quinazoline containing zinc-binding moiety based derivatives. The cyclodextrin is preferable a ?-cyclodextrin or a derivative thereof. The quinazolines have enhanced and unexpected properties as inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.