Hedgehog Pathway Antagonists
The Hedgehog pathway is known for its important role in inductive interactions that regulate growth and differentiation, and is likely also to play important roles in the homeostatic maintenance of post-embryonic tissue integrity. The present invention makes available reagents and methods for inhibiting activation of the hedgehog signaling pathway, e.g., to inhibit aberrant growth states, such as tumors, resulting from phenotypes such as ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function, comprising contacting the cell with an agent, such as a small molecule, in a sufficient amount to agonize a normal ptc activity, antagonize a normal hedgehog activity, or antagonize smoothened activity, e.g., to reverse or control the aberrant growth state. The present invention relates to the discovery that signal transduction pathways regulated by hedgehog, patched (ptc), gli and/or smoothened can be inhibited, at least in part, by small molecules. While not wishing to be prejudiced by any particular theory, the activation of a receptor may be the mechanism by which these agents act. For example, the ability of these agents to inhibit proliferation of patched loss-of-function (ptclof) cells may be due to the ability of such molecules to interact with hedgehog, patched, or smoothened, or at least to interfere with the ability of those proteins to activate a hedgehog, ptc, and/or smoothened-mediated signal transduction pathway. hedgehog antagonists of different structures, even ones that bind to the same protein in the hedgehog pathway, may act in slightly different ways. It is, therefore, specifically contemplated that these small molecules which interfere with aspects of hedgehog, ptc, or smoothened signal transduction activity will likewise be capable of inhibiting proliferation (or other biological consequences) in normal cells and/or cells having an aberrant phen Description (Set) Proposed Use (Set) The subject reagents and method may have therapeutic and cosmetic applications ranging from regulation of tumor formation, neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primitive gut, regulation of hematopoietic function, regulation of skin and hair growth, etc. Moreover, the subject methods can be performed on cells that are provided in culture (in vitro), or on cells in a whole animal (in vivo).Inventor(s): Beachy, Philip A.
Type of Offer: Licensing
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