PMID- 21698280
OWN - NLM
STAT- MEDLINE
DCOM- 20111107
LR  - 20240316
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 6
DP  - 2011
TI  - A novel synthetic smoothened antagonist transiently inhibits pancreatic 
      adenocarcinoma xenografts in a mouse model.
PG  - e19904
LID - 10.1371/journal.pone.0019904 [doi]
LID - e19904
AB  - BACKGROUND: Hedgehog (Hh) signaling is over-activated in several solid tumors 
      where it plays a central role in cell growth, stroma recruitment and tumor 
      progression. In the Hh signaling pathway, the Smoothened (SMO) receptor comprises 
      a primary drug target with experimental small molecule SMO antagonists currently 
      being evaluated in clinical trials. PRINCIPAL FINDINGS: Using Shh-Light II 
      (Shh-L2) and alkaline phosphatase (AP) based screening formats on a "focused 
      diversity" library we identified a novel small molecule inhibitor of the Hh 
      pathway, MS-0022 
      (2-bromo-N-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)benzamide). MS-0022 
      showed effective Hh signaling pathway inhibition at the level of SMO in the low 
      nM range, and Hh pathway inhibition downstream of Suppressor of fused (SUFU) in 
      the low microM range. MS-0022 reduced growth in the tumor cell lines PANC-1, SUIT-2, 
      PC-3 and FEMX in vitro. MS-0022 treatment led to a transient delay of tumor 
      growth that correlated with a reduction of stromal Gli1 levels in SUIT-2 
      xenografts in vivo. SIGNIFICANCE: We document the in vitro and in vivo efficacy 
      and bioavailability of a novel small molecule SMO antagonist, MS-0022. Although 
      MS-0022 primarily interferes with Hh signaling at the level of SMO, it also has a 
      downstream inhibitory effect and leads to a stronger reduction of growth in 
      several tumor cell lines when compared to related SMO antagonists.
FAU - Strand, Martin F
AU  - Strand MF
AD  - Unit for Cell Signalling, Institute for Microbiology, Oslo University Hospital, 
      Rikshospitalet, Oslo, Norway. martin.frank.strand@rr-research.no
FAU - Wilson, Steven R
AU  - Wilson SR
FAU - Dembinski, Jennifer L
AU  - Dembinski JL
FAU - Holsworth, Daniel D
AU  - Holsworth DD
FAU - Khvat, Alexander
AU  - Khvat A
FAU - Okun, Ilya
AU  - Okun I
FAU - Petersen, Dirk
AU  - Petersen D
FAU - Krauss, Stefan
AU  - Krauss S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110615
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (2-bromo-N-(4-(8-methylimidazo(1,2-a)pyridin-2-yl)phenyl)benzamide)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzamides)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Smo protein, mouse)
RN  - 0 (Smoothened Receptor)
SB  - IM
MH  - Adenocarcinoma/metabolism/*pathology
MH  - Animals
MH  - Antineoplastic Agents/pharmacokinetics/*pharmacology
MH  - Benzamides/pharmacokinetics/*pharmacology
MH  - Biological Availability
MH  - Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics/*pharmacology
MH  - Cell Division/drug effects
MH  - *Disease Models, Animal
MH  - Hedgehog Proteins/metabolism
MH  - Mice
MH  - Pancreatic Neoplasms/metabolism/*pathology
MH  - Receptors, G-Protein-Coupled/*antagonists & inhibitors
MH  - Signal Transduction
MH  - Smoothened Receptor
MH  - Transplantation, Heterologous
PMC - PMC3115942
COIS- Competing Interests: The chemotype detailed in this study is part of a patent 
      filed by Drs. Alex Khvat, Ilya Okun and others titled: HETEROCYCLIC INHIBITORS OF 
      AN Hh-SIGNAL CASCADE, MEDICINAL COMPOSITIONS BASED THEREON AND METHODS FOR 
      TREATING DISEASES CAUSED BY THE ABERRANT ACTIVITY OF AN Hh-SIGNAL SYSTEM 
      (PCT/IB2008/055258; WO 2009/077956 A2 and WO 2009/077956 A3). There are currently 
      no products arising from the work under development based on the chemotype 
      detailed in this study. None of the authors, aside from Drs. Alex Khvat, Ilya 
      Okun and Dan Holsworth who are employed by ChemDiv Inc, have any financial 
      relationships that could be perceived as relevant. The authors declare no other 
      competing interests. The competing interest detailed here does not alter the 
      authors' adherence to all the PLoS ONE policies on sharing data and materials.
EDAT- 2011/06/24 06:00
MHDA- 2011/11/08 06:00
PMCR- 2011/06/15
CRDT- 2011/06/24 06:00
PHST- 2010/03/18 00:00 [received]
PHST- 2011/04/20 00:00 [accepted]
PHST- 2011/06/24 06:00 [entrez]
PHST- 2011/06/24 06:00 [pubmed]
PHST- 2011/11/08 06:00 [medline]
PHST- 2011/06/15 00:00 [pmc-release]
AID - 10-PONE-RA-17246 [pii]
AID - 10.1371/journal.pone.0019904 [doi]
PST - ppublish
SO  - PLoS One. 2011;6(6):e19904. doi: 10.1371/journal.pone.0019904. Epub 2011 Jun 15.