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Non-alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease and is associated with metabolic dysregulation. Although G protein-coupled receptor 84 (GPR84) has been associated with inflammation, its role in metabolic regulation remains elusive. The aim of our study was to evaluate the potential of PBI-4547 for the treatment of NAFLD and to validate the role of its main target receptor, GPR84. We report that PBI-4547 is a fatty acid mimetic, acting concomitantly as a GPR84 antagonist and GPR40/GPR120 agonist. In a mouse model of diet-induced obesity, PBI-4547 treatment improved metabolic dysregulation, reduced hepatic steatosis, ballooning and NAFLD score. PBI-4547 stimulated fatty acid oxidation and induced gene expression of mitochondrial uncoupling proteins in the liver. Liver metabolomics revealed that PBI-4547 improved metabolic dysregulation induced by a high-fat diet regimen. In Gpr84−/− mice, PBI-4547 treatment failed to improve various key NAFLD-associated parameters, as was observed in wildtype littermates. Taken together, these results highlight a detrimental role for the GPR84 receptor in the context of meta-inflammation and suggest that GPR84 antagonism via PBI-4547 may reflect a novel treatment approach for NAFLD and its related complications.

Low‐molecular‐weight synthetic molecules 1 with the general 2‐(fluorophenylamino)‐4,6‐disubstituted 1,3,5‐triazine structure and showing anti‐inflammatory and anticancer activities were explored. Structure–activity relationship studies demonstrated the importance of the aminopentyl chain, the 3‐ or 4‐fluorophenylaniline component, and the presence of at least one substituent, such as a tyramine moiety, attached directly to the triazine ring as essential for good activity. These compounds, represented by leads 4‐{2‐[4‐(5‐Aminopentylamino)‐6‐(3‐fluorophenylamino)‐1,3,5‐triazin‐2‐ylamino]ethyl}phenol (6) and 4‐{2‐[4‐(5‐Aminopentylamino)‐6‐(4‐fluorophenylamino)‐1,3,5‐triazin‐2‐ylamino]ethyl}phenol (10), displayed moderate and significant in vitro and in vivo dual activities, respectively, and address the molecular link between inflammation and cancer. Compound 10 demonstrated significant antitumor efficacy upon administration by the oral and intravenous routes in several animal models. This class of triazine compounds is new, safe, and nontoxic and offers a novel approach to the treatment of inflammation and cancer.

Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein–coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although GPR40 and GPR84 are involved in diverse physiological processes, no evidence has demonstrated the relevance of GPR40 and GPR84 in fibrosis pathways. Using PBI-4050 (3-pentylbenzeneacetic acid sodium salt), a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, respectively, we uncovered an antifibrotic pathway involving these receptors. In experiments using Gpr40 - and Gpr84 -knockout mice in models of kidney fibrosis (unilateral ureteral obstruction, long-term post-acute ischemic injury, and adenine-induced chronic kidney disease), we found that GPR40 is protective and GPR84 is deleterious in these diseases. Moreover, through binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in many injury contexts, as evidenced by the antifibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models. Therefore, GPR40 and GPR84 may represent promising molecular targets in fibrosis pathways. We conclude that PBI-4050 is a first-in-class compound that may be effective for managing inflammatory and fibrosis-related diseases.

Introduction and Aims: Given the expected rise in the prevalence of obesity and type 2 diabetes, hepatic steatosis will, if not already, become an epidemic. The aim of this study was to determine the mechanism of action of PBI-4547 on diabetic complications. Methods: ob/ob mice (6 weeks old) were treated with vehicle or PBI-4547 (10, 25 and 50 mg/kg, oral once a day) from day 1 through 105. Liver and white adipose tissue (WAT) histology, blood glucose, serum triglyceride and adiponectin levels were examined. Gene expression of pro-inflammatory/fibrotic markers, metabolic and mitochondrial fatty acid transport and oxidation (FAO) regulators, and PPAR gene expression were determined in liver and WAT. Results: Blood glucose, cholesterol and triglyceride levels were strongly reduced by PBI-4547. ob/ob mice displayed severe liver steatosis which was completely reversed with PBI-4547. PBI-4547 significantly reduced fibrosis, inflammatory cell infiltration, and adipocyte size in WAT. Serum level of adiponectin was reduced in ob/ob mice and increased with PBI-4547. In liver, PBI-4547 reduced TNF-α, collagen I, III and IV, α-SMA, fibronectin, MMP-2, TIMP1, ICAM, PDGFα, TGFβ1, PPARδ and PPARγ, FASN, but increased mitochondrial FA transport and oxidation (ACOX-1, CD36, FABP4, CPT1β, PDK4). In WAT, PBI-4547 reduced TNF-α, collagen types I, IV and VI, MMP-2, MCP-1, F4/80, increased PPARα and PPARγ, and also increased ACOX-1, CD36, FASN, FABP4, COX4I1, SREBF1, PGC1-α, UCP-1 (by 160X, suggesting browning of adipose tissue), CPT1α, CPT1β and PDK4. Furthermore, PBI-4547 increased adiponectin and its receptors, and abolished vaspin gene expression. Conclusions: PBI-4547 is a potential novel therapy for diabetes and hepatic steatosis through its pleiotropic activities on glucose and lipid metabolism, by improving mitochondrial dysfunction, by inducing browning of adipose tissue, and by regulating adipokines. Disclosure L. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Laverdure: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F. Sarra-Bournet: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Cloutier: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Felton: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Tremblay: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Richard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gervais: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. P. Laurin: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc.. Board Member; Self; Prometic Life Sciences Inc. F.A. Leblond: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc..

Introduction and Aims: Obesity and its resulting metabolic disturbances are major health threats and are the main cause of a host of diseases, including nonalcoholic fatty liver disease (NAFLD). PBI-4547 is a novel first-in-class orally active antidiabetic compound which displays pleiotropic activities and has been shown to reduce NASH, diabetes, and renal fibrosis in different animal models. The aim of this study was to investigate the effects of PBI-4547 in a mouse model of high-fat diet-induced obesity and metabolic syndrome. Methods: C57BL/6 mice were fed with either a standard or a high-fat diet (HFD, Harlan, TD.06414) for 14 weeks. These mice were divided in three groups [normal chow, HFD + vehicle, and HFD + PBI-4547 (10 mg/kg, oral once a day)] and treated for an additional 6 weeks. Blood glucose, serum insulin level, serum triglyceride and adiponectin, liver histology, as well as liver and white adipose tissue (WAT) pro-inflammatory/fibrotic gene expression were examined. Results: In an oral glucose tolerance test, PBI-4547 increased glucose metabolism compared to the HFD control group. Insulin resistance (measured by HOMA-IR) and β cell function (HOMA1-β) were improved by PBI-4547. Serum triglyceride level was significantly reduced by PBI-4547 while adiponectin in serum was significantly increased. Histological analysis showed a significant reduction of hepatic steatosis and ballooning by PBI-4547. To further characterize the activity of PBI-4547, quantitative RT-PCR analysis of pro-fibrotic markers was performed, demonstrating that PBI-4547 reduced CTGF and MMP2 gene expression in the liver as well as CTGF, MCP-1, MMP2 and collagen type I gene expression in the WAT. Conclusions: Taken together, these results suggest that PBI-4547 offers the potential as a novel therapy for nonalcoholic fatty liver disease, obesity and associated metabolic syndrome. Disclosure M. Leduc: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Tremblay: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gervais: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F. Sarra-Bournet: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Felton: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Simard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F.A. Leblond: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. P. Laurin: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc.. Board Member; Self; Prometic Life Sciences Inc. L. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc..

Background: PBI-4050 displays anti-inflammatory/fibrotic properties with metabolic regulation. PBI-4050 has been shown to reduce glycated hemoglobin levels, and different biomarkers related to kidney and heart injury in a phase II open label clinical trial in patients suffering from type 2 diabetes with metabolic syndrome. PBI-4050 has also completed with success an open label phase II clinical trial in patients with idiopathic pulmonary fibrosis (IPF) and in patients with Alström Syndrome. The aim of this study was to investigate the effect of PBI-4050 on diabetic nephropathy in leptin deficient ob/ob mice, a model of type 2 diabetes and metabolic syndrome. Methods: ob/ob mice were treated with vehicle or PBI-4050 (200 mg/kg, oral once a day) from day 1 to 105. OGTT, triglycerides, adiponectin and serum insulin levels, as well as inflammatory cell infiltration and pro-inflammatory/fibrotic gene expression and histology of kidney and white adipose tissue (WAT) were examined. Results: PBI-4050 improved glucose metabolism, reduced serum triglycerides and insulin levels, and increased serum adiponectin levels. In kidneys, PBI-4050 reduced ER stress (p-PERK, ATF-6, CHOP and p-IRE1). Furthermore, PBI-4050 reduced α-SMA, fibronectin and CTGF gene expression. Pro-inflammatory/remodeling markers expression (MRC-1, MCP-1 and MMP-2) were also reduced with PBI-4050 treatment. Moreover, histological analysis revealed that PBI-4050 reduced collagen deposition in glomeruli. Specific immunostaining also showed that PBI-4050 significantly reduced galectin-3 expression in kidney and WAT. Finally, PBI-4050 reduced the expression levels of inflammatory cell infiltration markers (Ly6G and F4/80) in kidney. Conclusions: These results suggest that PBI-4050 is a strong potential candidate for the treatment of metabolic diseases and related diabetic nephropathy. Disclosure J. Simard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Cloutier: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Laverdure: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Richard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gervais: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Felton: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. P. Laurin: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc.. Board Member; Self; Prometic Life Sciences Inc. M. Leduc: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F.A. Leblond: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc..

Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein-coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although GPR40 and GPR84 are involved in diverse physiological processes, no evidence has demonstrated the relevance of GPR40 and GPR84 in fibrosis pathways. Using PBI-4050 (3-pentylbenzeneacetic acid sodium salt), a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, respectively, we uncovered an antifibrotic pathway involving these receptors. In experiments using Gpr40- and Gpr84-knockout mice in models of kidney fibrosis (unilateral ureteral obstruction, long-term post-acute ischemic injury, and adenine-induced chronic kidney disease), we found that GPR40 is protective and GPR84 is deleterious in these diseases. Moreover, through binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in many injury contexts, as evidenced by the antifibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models. Therefore, GPR40 and GPR84 may represent promising molecular targets in fibrosis pathways. We conclude that PBI-4050 is a first-in-class compound that may be effective for managing inflammatory and fibrosis-related diseases.

PBI-4050 is a first-in-class orally active compound which displays antifibrotic activities in kidney, heart, liver, pancreas and lung models. PBI-4050 was found to be safe and well tolerated in healthy volunteers and in patients with CKD and Type 2 diabetes without any SAEs. Translation of pharmacological efficacy in humans …

Background: PBI-1402 reduces the need for transfusion and increases hemoglobin (Hb) level and red blood cell count (RBC) in chemotherapy-induced anemia (CIA) patients by a mechanism of action which is distinct from erythropoietin (EPO). The PBI-1402 receptor is also expressed on certain cancer cells such as leukemia (K562), lung (LL-2), prostate (PC-3) and pancreas (Panc-02). Aim: The objective of this study was to determine the role of the PBI-1402 receptor on tumor growth. Methods: Cell proliferation and differentiation of K562 (human erythroleukemia) was studied in presence of PBI-1402 or EPO using 2,7-diaminofluorene for hemoglobin quantification. The effect of oral administration of PBI-1402 in combination with chemotherapy agents (gemcitabine or cyclophosphamide) was studied in subcutaneous syngeneic Panc02, LL-2 and xenogeneic PC-3 models. Results: PBI-1402 inhibits proliferation of K562 cells and promotes differentiation of the remaining cells. K562 cells express both EPO and PBI-1402 receptors. EPO increases phosphorylation of ERK1/2 and Stat3 (linked to cell proliferation) while PBI-1402 decreases it in a dose dependent manner. The antitumor efficacy of oral administration of PBI-1402 was studied in combination with gemcitabine in subcutaneous LL2 and Panc02 as well as in orthotopic Panc02 cancers. In subcutaneous Panc02, gemcitabine induced a significant inhibition (p Conclusion: These results suggest that PBI-1402 has the potential to inhibit the growth of lung, prostate and pancreatic cancer by induction of cell differentiation. PBI-1402-differentiated cancer cells appear to be more susceptible to chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3534. doi:10.1158/1538-7445.AM2011-3534