Exo-cyclopamine--a stable and potent inhibitor of hedgehog-signaling.

The combination of theoretical and computational studies with organic synthesis and biological investigations has led to exo-cyclopamine. This stable and highly potent derivative of cyclopamine promises big potential as an experimental drug against several types of human cancer.

Modulators of the hedgehog signaling pathway.

Since its discovery by C. Nüsslein-Volhard and E. F. Wieschaus, hedgehog (hh) signaling has come a long way. Today it is regarded as a key regulator in embryogenesis where it governs processes like cell proliferation, differentiation, and tissue patterning. Furthermore, in adults it is involved in the maintenance of stem cells, and in tissue repair and regeneration. But hh signaling has a second-much darker-face: it plays an important role in several types of human cancers where it promotes growth and enables proliferation of tumor stem cells. The etiology of medulloblastoma and basal cell carcinoma is tightly linked to aberrant hh activity, but also cancers of the prostate, the pancreas, the colon, the breasts, rhabdomyosarcoma, and leukemia, are dependent on irregular hh activity. Recent clinical studies have shown that hh signaling can be the basis of an important new class of therapeutic agents with far-reaching implications in oncology. Thus, modulation of hh signaling by means of small molecules has emerged as a valuable tool in combating these hh-dependent cancers. Cyclopamine, a unique natural product with a fascinating history, was the first identified inhibitor of hh signaling and its story is closely linked to the progress in the whole field. In this review we will trace the story of cyclopamine, give an overview on the biological modes of hh signaling both in untransformed and malignant cells, and finally present potent modulators of the hh pathway-many of them already in clinical studies. For more than 30 years now the knowledge on hh signaling has grown steadily-an end to this development is far from being conceivable.

Serotonin derivatives as a new class of non-ATP-competitive receptor tyrosine kinase inhibitors.

The discovery of new templates and their subsequent elaboration to clinically useful receptor tyrosine kinase (RTK) inhibitors continues to be an important issue. RTKs are a class of enzymes responsible for the activation of different cellular signal transduction cascades. The majority of the known small molecules RTK inhibitors are ATP-competitive and they are multiple targeted inhibitors. We describe here serotonin derivatives as a new class of multiple targeted RTK inhibitors. In contrast to most other RTK inhibitors they act via a non-ATP-competitive (allosteric) mechanism. Furthermore, they are able to inhibit the proliferation of HUVE cells, fibroblasts and two cancer cell lines.

Cyclopamine and hedgehog signaling: chemistry, biology, medical perspectives.

When Odysseus left the devastated city of Troy after ten years of siege he could not foresee the perils he still had to face. The encounter with the cyclops, a giant with only one eye placed in the middle of its forehead, was doubtlessly one of the creepiest and most dangerous of his adventures. In the end, Odysseus could only escape with the help of a sheep. Whether Homers cyclops was inspired by the observation of terribly malformed neonates remains speculative. However, when sheep herders in Idaho in the middle of the 20th century faced an increasing number of cyclops-like sheep in their herds, a unique cascade of chemical, biological, and medicinal discoveries was initiated. This Minireview tells this story and shows its impact on modern biomedical research.

Synthesis and biological evaluation of SANT-2 and analogues as inhibitors of the hedgehog signaling pathway.

Hedgehog (Hh) signaling plays an important role in cell signaling of embryonic development and adult tissue homeostasis. In vertebrates, the hh gene encodes three different unique proteins: sonic hedgehog (Shh), desert hedgehog (Dhh) and indian hedgehog (Ihh). Disruption of the Hh signaling pathway leads to severe disorders in the development of vertebrates whereas aberrant activation of the Hh pathway has been associated with several malignancies including Gorlin syndrome (a disorder predisposing to basal cell carcinoma, medulloblastoma and rhabdomyosarcoma), prostate, pancreatic and breast cancers. In vivo evidence suggests the antagonism of excessive Hh signaling provides a route to unique mechanism-based anti-cancer therapies. Recently the small molecule SANT-2 was identified as a potent antagonist of Hh-signaling pathway. Here, we describe the synthesis, SAR studies as well as biological evaluation of SANT-2 and its analogues. Fifteen SANT-2 derivatives were synthesized and analyzed for their interference with the expression of the Hh target gene Gli1 in a reporter gene assay. By comparison of structure and activity important molecular descriptors for Gli inhibition could be identified. Furthermore we identified derivative TC-132 that was slightly more potent than the parent compound SANT-2. Selected compounds were tested for Hh related teratogenic effects in the small teleost model medaka. Albeit Gli expression has indicated a 16-fold higher Hh-inhibiting activity than observed for the plant alkaloid cyclopamine, none of the tested compounds were able to induce the cyclopamine-specific phenotype in the medaka assay.