Author: Schett, Georg ; Hsieh, Mindy H ; Li, Chun ; Beyer, Christian ; Svensson, Eric C ; Ng, Nicholas ; Althage, Alana ; Distler, Jörg H W ; Trinh-Minh, Thuong ; Meeusen, Shelly ; Xu, Xiaohan ; Chen, Chih-Wei ; Liu, Jun ; Cole, Stuart H ; Pan, Shifeng ; Harris, Jennifer L ; Gergely, Peter ; Seidel, H Martin ; Maier, Christiane

ObjectivesWnt signalling has been implicated in activating a fibrogenic programme in fibroblasts in systemic sclerosis (SSc). Porcupine is an O-acyltransferase required for secretion of Wnt proteins in mammals. Here, we aimed to evaluate the antifibrotic effects of pharmacological inhibition of porcupine in preclinical models of SSc.MethodsThe porcupine inhibitor GNF6231 was evaluated in the mouse models of bleomycin-induced skin fibrosis, in tight-skin-1 mice, in murine sclerodermatous chronic-graft-versus-host disease (cGvHD) and in fibrosis induced by a constitutively active transforming growth factor-β-receptor I.ResultsTreatment with pharmacologically relevant and well-tolerated doses of GNF6231 inhibited the activation of Wnt signalling in fibrotic murine skin. GNF6231 ameliorated skin fibrosis in all four models. Treatment with GNF6231 also reduced pulmonary fibrosis associated with murine cGvHD. Most importantly, GNF6231 prevented progression of fibrosis and showed evidence of reversal of established fibrosis.ConclusionsThese data suggest that targeting the Wnt pathway through inhibition of porcupine provides a potential therapeutic approach to fibrosis in SSc. This is of particular interest, as a close analogue of GNF6231 has already demonstrated robust pathway inhibition in humans and could be available for clinical trials.

14 Jul 2016·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Discovery of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors

Q3 · MEDICINE

Article

Author: Zhang, Guobao ; Steffy, Auzon ; Li, Chun ; Pan, Shifeng ; Harris, Jennifer L. ; Li, Jie ; Cheng, Dai ; Sun, Fangxian ; Hsieh, Mindy H. ; Tompkins, Celin ; Ng, Nicholas ; Han, Dong ; Gao, Wenqi ; Seidel, H. Martin ; Liu, Jun ; Kasibhatla, Shailaja

Blockade of aberrant Wnt signaling is an attractive therapeutic approach in multiple cancers. We developed and performed a cellular high-throughput screen for inhibitors of Wnt secretion and pathway activation. A lead structure (GNF-1331) was identified from the screen. Further studies identified the molecular target of GNF-1331 as Porcupine, a membrane bound O-acyl transferase. Structure-activity relationship studies led to the discovery of a novel series of potent and selective Porcupine inhibitors. Compound 19, GNF-6231, demonstrated excellent pathway inhibition and induced robust antitumor efficacy in a mouse MMTV-WNT1 xenograft tumor model.

Cell, Stem cells and Regenerative Medicine

Temporary, Systemic Inhibition of the WNT/β-Catenin Pathway promotes Regenerative Cardiac Repair following Myocardial Infarct

Article

Author: Young, Pampee P ; Saraswati, Sarika ; Harris, Jennifer L ; Feoktistov, Igor ; Atkinson, James ; Liu, Jun ; Bastakoty, Dikshya ; Joshi, Piyush

AIMSThe WNT/β-catenin pathway is temporarily activated in the heart following myocardial infarction (MI). Despite data from genetic models indicating both positive and negative roles for the WNT pathway depending on the model used, the effect of therapeutic inhibition of WNT pathway on post-injury outcome and the cellular mediators involved are not completely understood. Using a newly available, small molecule, GNF-6231, which averts WNT pathway activation by blocking secretion of all WNT ligands, we sought to investigate whether therapeutic inhibition of the WNT pathway temporarily after infarct can mitigate post injury cardiac dysfunction and fibrosis and the cellular mechanisms responsible for the effects.METHODS AND RESULTSPharmacologic inhibition of the WNT pathway by post-MI intravenous injection of GNF-6231 in C57Bl/6 mice significantly reduced the decline in cardiac function (Fractional Shortening at day 30: 38.71 ± 4.13% in GNF-6231 treated vs. 34.89 ± 4.86% in vehicle-treated), prevented adverse cardiac remodeling, and reduced infarct size (9.07 ± 3.98% vs. 17.18 ± 4.97%). WNT inhibition augmented proliferation of interstitial cells, particularly in the distal myocardium, inhibited apoptosis of cardiomyocytes, and reduced myofibroblast proliferation in the peri-infarct region. In vitro studies showed that WNT inhibition increased proliferation of Sca1⁺ cardiac progenitors, improved survival of cardiomyocytes, and inhibited collagen I synthesis by cardiac myofibroblasts.CONCLUSIONSystemic, temporary pharmacologic inhibition of the WNT pathway using an orally bioavailable drug immediately following MI resulted in improved function, reduced adverse remodeling and reduced infarct size in mice. Therapeutic WNT inhibition affected multiple aspects of infarct repair: it promoted proliferation of cardiac progenitors and other interstitial cells, inhibited myofibroblast proliferation, improved cardiomyocyte survival, and reduced collagen I gene expression by myofibroblasts. Our data point to a promising role for WNT inhibitory therapeutics as a new class of drugs to drive post-MI repair and prevent heart failure.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	Novartis AG	26 Jan 2016

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