Targeting the hedgehog signaling pathway with small molecules.
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.
Kiselyov
Alex S
AS
Small Molecule Drug Discovery, ChemDiv, Inc., 11558 Sorrento Valley Rd., Suite 5, San Diego, CA 92121, US. ask@chemdiv.com
D000818:Animals; D004149:Dioxoles / Q000494:pharmacology; D029721:Drosophila Proteins / Q000187:drug effects / Q000502:physiology; D053823:Hedgehog Proteins / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D009369:Neoplasms / Q000209:etiology; D000072079:Patched Receptors; D010879:Piperazines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids / Q000494:pharmacology
C474318:CUR 61414; D004149:Dioxoles; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D010879:Piperazines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; C100664:smo protein, Drosophila; C000541:cyclopamine