cur-61414 and Neoplasms

Topics: Antineoplastic Agents; Drug Discovery; Hedgehog Proteins; Humans; Neoplasms; Signal Transduction; Transcription Factors; Zinc Finger Protein GLI1

In addition to the potential stem cells offer for regenerative medicine, they also rapidly are becoming a center of focus in oncology. There are several developmental pathways that are involved in the deregulated signaling in stem cells resulting in tumorigenesis. For example, aberrant activation of the Hedgehog (Hh) pathway has been associated with numerous malignancies including basal cell carcinoma, medulloblastoma, prostate, pancreatic and breast cancers. In vivo evidence suggests the antagonism of excessive Hh signaling may provide a route to unique mechanism-based anti-cancer therapies. This review summarizes recent developments in targeting cell-surface proteins and intracellular targets from the Hh pathway with small molecules. Hh signaling is triggered by lipid-modified Hh proteins that exert their activity via a series of transmembrane receptors (Patched, Ptc and Smoothened, Smo). Smoothened (Smo) is a 7-TM protein reported to be the most druggable target in the Hh signaling cascade. We further review several published programs geared towards identification and profiling of synthetic antagonists of Smo. Challenges and perspectives of this approach are also discussed.

Topics: Animals; Dioxoles; Drosophila Proteins; Hedgehog Proteins; Humans; Neoplasms; Patched Receptors; Piperazines; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Signal Transduction; Smoothened Receptor; Veratrum Alkaloids

The seven-transmembrane receptor Smoothened (Smo) transduces the signal initiated by Hedgehog (Hh) morphogen binding to the receptor Patched (Ptc). We have reinvestigated the pharmacological properties of reference molecules acting on the Hh pathway using various Hh responses and a novel functional assay based on the coexpression of Smo with the alpha subunit of the G15 protein in HEK293 cells. The measurement of inositol phosphate (IP) accumulation shows that Smo has constitutive activity, a response blocked by Ptc which indicates a functional Hh receptor complex. Interestingly, the antagonists cyclopamine, Cur61414, and SANT-1 display inverse agonist properties and the agonist SAG has no effect at the Smo-induced IP response, but converts Ptc-mediated inactive forms of Smo into active ones. An oncogenic Smo mutant does not mediate an increase in IP response, presumably reflecting its inability to reach the cell membrane. These studies identify novel properties of molecules displaying potential interest in the treatment of various cancers and brain diseases, and demonstrate that Smo is capable of signaling through G15.

Topics: Animals; Cell Cycle Proteins; Cell Line; Cell Membrane; Dioxoles; DNA-Binding Proteins; Genes, Tumor Suppressor; Hedgehog Proteins; Humans; Mice; Neoplasms; Piperazines; Pyrazoles; Receptors, G-Protein-Coupled; RNA-Binding Proteins; Signal Transduction; Smoothened Receptor; Stem Cells; Trans-Activators; Tumor Suppressor Proteins; Veratrum Alkaloids