Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=24994715
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Pyrvinium attenuates Hedgehog signaling downstream of smoothened
#MMPMID24994715
Li B
; Fei DL
; Flaveny CA
; Dahmane N
; Baubet V
; Wang Z
; Bai F
; Pei XH
; Rodriguez-Blanco J
; Hang B
; Orton D
; Han L
; Wang B
; Capobianco AJ
; Lee E
; Robbins DJ
Cancer Res
2014[Sep]; 74
(17
): 4811-21
PMID24994715
show ga
The Hedgehog (HH) signaling pathway represents an important class of emerging
developmental signaling pathways that play critical roles in the genesis of a
large number of human cancers. The pharmaceutical industry is currently focused
on developing small molecules targeting Smoothened (Smo), a key signaling
effector of the HH pathway that regulates the levels and activity of the Gli
family of transcription factors. Although one of these compounds, vismodegib, is
now FDA-approved for patients with advanced basal cell carcinoma, acquired
mutations in Smo can result in rapid relapse. Furthermore, many cancers also
exhibit a Smo-independent activation of Gli proteins, an observation that may
underlie the limited efficacy of Smo inhibitors in clinical trials against other
types of cancer. Thus, there remains a critical need for HH inhibitors with
different mechanisms of action, particularly those that act downstream of Smo.
Recently, we identified the FDA-approved anti-pinworm compound pyrvinium as a
novel, potent (IC50, 10 nmol/L) casein kinase-1? (CK1?) agonist. We show here
that pyrvinium is a potent inhibitor of HH signaling, which acts by reducing the
stability of the Gli family of transcription factors. Consistent with CK1?
agonists acting on these most distal components of the HH signaling pathway,
pyrvinium is able to inhibit the activity of a clinically relevant, vismodegib
-resistant Smo mutant, as well as the Gli activity resulting from loss of the
negative regulator suppressor of fused. We go on to demonstrate the utility of
this small molecule in vivo, against the HH-dependent cancer medulloblastoma,
attenuating its growth and reducing the expression of HH biomarkers.
free
free
free
