Inhibitor SourceBook™ Second Edition

Other Inhibitors of Biological Interest
Sonic Hedgehog Signaling Inhibitors
Mammalian Hedgehog proteins include Sonic Hedgehog
(Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh).
Shh is expressed mainly in the epithelia in the tooth, hair,
whisker, gut, bladder, urethra, vas deferens, and lung, Dhh
is found in Schwann and Sertoli cell precursors and Ihh is
expressed in gut and cartilage. Hedgehog proteins undergo
autocatalysis to generate a ~20 kDa N-terminal domain
and a ~25 kDa C-terminal domain. This autoprocessing
causes the covalent attachment of cholesterol onto the
carboxy-terminus of the N-terminal domain. The Nterminal
domain retains all signaling capabilities while the
C-terminal domain is responsible for the intramolecular
precursor processing. The cholesterol moiety is believed
to be responsible for directing Hedgehog traffic in the
secretory cell.
Shh, a secreted morphogen, has been implicated in several
embryonic developmental processes. It displays inductive,
proliferative, neurotrophic, and neuroprotective properties.
Shh often works in concert with the Wnt signaling protein
in setting embryonic patterns. The Wnt pathway uses bcatenin
to transduce its signals to the nucleus; however,
the Shh pathway utilizes a 155 amino acid protein, Cubitus
interruptus (Ci155) in Drosophila or Gli in mammals. In
the absence of a Shh signal, Ci is targeted for proteolysis,
which generates a truncated 75-amino acid residues form
(Ci75) that acts as a transcriptional repressor. In vertebrates
three Gli proteins (Gli1, Gli2, and Gli3) have been reported.
Despite several homologous regions, including a DNAbinding
domain with five C2-H2 zinc fingers and a Cterminal
transcription activation domain, these proteins
have distinct activities and are not considered to be
functionally equivalent.
Sonic Hedgehog Signaling Inhibitors
Shh signaling is known to occur through a receptor
complex associating two membrane proteins, Patched (Ptc)
and Smoothened (Smo). Ptc is a twelve-pass membrane
protein that acts as a receptor and binds Hedgehog ligand;
Smo is a seven-pass membrane protein that acts as a signal
transducer. In the absence of a ligand, Ptc interacts with
Smo and inhibits its activity. Shh binding to Ptc removes
the inhibitory effect and allows Gli to enter the nucleus and
act as a transcriptional activator. Shh signaling is required
throughout embryonic development and is involved in the
determination of cell fate and embryonic patterning during
early vertebrate development. During the late stage of
development, Shh is involved in the proper formation of a
variety of tissues and organs. Shh also functions with other
signaling molecules such as the fibroblast growth factors
and bone morphogenetic protein to mediate developmental
processes. Mutations in any of the components of the
Shh pathway can lead to congenital defects and diseases,
including cancer. Hence, the Shh pathway has become a
potential target for drug development for the treatment of
cancers and degenerative diseases.
References:
Lum, L., and Beachy, P.A. 2004. Science 304, 755.
Wetmore, C. 2003. Curr. Opin. Genet. Dev. 13, 34.
Pola, R., et al. 200 . Nat. Med. 7, 706.
Chuong, C.M., et al. 2000. Cell. Mol. Life Sci.57, 692.
McMahon, A.P. 2000. Cell 100, 85.
Pepinsky, R.B., et al. 998. J. Biol. Chem. 273, 4037.
Porter, J.A., et al. 996. Science 274, 255.
More online... www.calbiochem.com/inhibitors/Shh
Product Cat. No. Comments Size Price
AY 9944 190080 A cell-permeable inhibitor of 7-dehydrocholesterol reductase
(D7-sterol reductase). Also reported to induce a rapid and irreversible
reduction in acidic-sphingomyelinase activity in fibroblasts.
Cyclopamine, V. californicum 239803 A steroidal alkaloid and cholesterol mimic that disrupts cholesterol
bio-synthesis and specifically antagonizes Shh signaling through
direct interaction with Smo (smoothened).
N Cyclopamine-KAAD 239804 [KAAD-Cyclopamine; 3-Keto-N-(aminoethyl-aminocaproyl-dihydro-
cinnamoyl)cyclopamine]
A potent, cell-permeable analog of Cyclopamine (Cat. No. 239803)
that inhibits the Hedgehog signaling with similar or lower toxicity
(IC 50 = 20 nM in Shh-LIGHT2 assay).
Jervine 420210 [(3b, 23b)-17,23-Epoxy-3-hydroxyveratraman-11-one; 11-
Ketocyclopamine]
A cell-permeable inhibitor that induces cyclopia by blocking Shh
signaling (IC 50 = 500 –700 nM in S 2 cells).
5 mg $ 5
mg $ 2
00 mg $ 32
mg $95
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