Modulating the Hedgehog pathway

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-(8methylimidazo[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 mM 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. Citation: Strand MF, Wilson SR, Dembinski JL, Holsworth DD, Khvat A, et al. (2011) A Novel Synthetic Smoothened Antagonist Transiently Inhibits Pancreatic Adenocarcinoma Xenografts in a Mouse Model. PLoS ONE 6(6): e19904. doi:10.1371/journal.pone. 0019904 Editor: Eric J. Bernhard, National Cancer Institute, United States of America Received March 18, 2010; Accepted April 20, 2011; Published June 15, 2011 Copyright: 2011 Strand et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was funded by the Research Council of Norway (http://www.forskningsradet.no/), and by ChemDiv Inc. (http://www.chemdiv.com/). The Research Council of Norway had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. As indicated under the competing interests section, Drs. Alex Khvat, Ilya Okun and Dan Holsworth are employed by ChemDiv Inc., and ChemDiv Inc. had a partial role in the study design, execution of the experiments, data analysis, and decision to publish and in reviewing the manuscript. The MS-0022 chemotype has been patented by ChemDiv Inc. (PCT/IB2008/055258; WO 2009/077956 A2 and WO 2009/077956 A3). 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. * E-mail: martin.frank. strand@rr-research.no (MFS); stefan.krauss@rr-research.no (SK)