Structural analogues of smoothened intracellular loops as potent inhibitors of Hedgehog pathway and cancer cell growth.
Smoothened is a critical component of the Hedgehog pathway that is essential for stem cell renewal and is dysregulated in many cancer types. We have found synthetic analogues of the second and third intracellular loops of smoothened to be potent inhibitors of the Hedgehog pathway. Palmitoylated peptides as short as 10 residues inhibited melanoma cells growth with IC50 in the low nanomolar range. The compounds are promising drug candidates and convenient tools for solving mechanisms of Hedgehog signaling.
Molecular Aspects of Drug Design Section, Structural Biophysics Laboratory, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA.
Jarrett R
JR
Remsberg
Hong
H
Lou
Sergey G
SG
Tarasov
Michael
M
Dean
Nadya I
NI
Tarasova
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017124:Conserved Sequence; D004354:Drug Screening Assays, Antitumor; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010169:Palmitic Acids / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D013329:Structure-Activity Relationship
D053823:Hedgehog Proteins; D009842:Oligopeptides; D010169:Palmitic Acids; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor