First-in-class small molecule therapeutics to enhance gut barrier function in inflammatory bowel diseasePA-20-260, R43 Phase I SBIRPI: Frederick M. Ausubel Inflammatory Bowel Disease (IBD), which affects approximately to 3 million Americans, is characterized bychronic relapsing inflammation and barrier dysfunction, manifested as enhanced permeability of the intestinalepithelium caused by a breakdown of tight junction proteins between cells. Because FDA-approved IBDtherapeutics target inflammation rather than barrier dysfunction, there is a current need for an orally available,non-toxic, non-immunosuppressive IBD therapeutic that directly enhances barrier function and blocksprogression to more severe forms of IBD. Artus Therapeutics is developing IBD therapeutics inspired by thenatural microbiome compound urolithin A (UroA). UroA exhibits anti-inflammatory activity and a highly favorabletoxicity profile in rodents and humans, but its lack of stability at low pH is a major impediment for its furtherdevelopment. Artus therapeutics has synthesized a urolithin analog, ARTX-2, that is significantly more acidstable and more resistant to hydrolysis by digestive enzymes than UroA. Published and preliminary data showthat oral administration of ARTX-2 dramatically mitigates the symptoms of dextran sodium sulphate (DSS) or2,4,6-Trinitrobenzenesulfonic acid (TNBS) induced ulcerative colitis in mice. Further, ARTX-2 up-regulates tightjunction proteins (TJPs) including Claudin4 and Occludin in gut epithelium as well as blocks LPS-inducedinflammatory cytokines in bone marrow derived macrophages (BMDMs). Genetic analysis in mice shows thatthe bioactivity of ARTX-2 is dependent upon the aryl hydrocarbon receptor (AhR) and the nuclear transcriptionfactor (erythroid-derived 2)-like 2 (Nrf2). Based on these observations, it was concluded ARTX-2 mitigates IBDthrough activation of AhR-dependent pathways at two distinct levels: by (i) preserving and/or enhancing gutbarrier function and (ii) reducing systemic and acute inflammation by downregulating inflammatory cytokines inimmune cells. Based on the promising data with ARTX-2, 44 more ARTX-2 analogs have been synthesized andpreliminary data show that some of these analogs appear to be more potent than ARTX-2 in blocking theproduction of inflammatory cytokines in BMDMs. In this SBIR Phase I application, we propose lead optimizationof ARTX-2. In Aim 1, we will compare ARTX-2 and 44 ARTX-2 analogs with respect to: 1) upregulation of TJPs:2) decrease in epithelial permeability; and 3) downregulation of cytokines. Up to 10 analogs that are equally ormore potent than ARTX-2 will be further tested for their efficacy in dose-response assays. In Aim 2, we will carryout efficacy studies in the mouse TNBS chemically-induced model of ulcerative coliits for the top 5 prioritizedcompounds from Aim 1. For the 3 most efficacious compounds in the mouse TNBS model, we will further testfor efficacy in the mouse DSS chemically-induced model of ulcerative colitis. The overall goal of the proposedproject is to identify 2-3 ARTX-2 analogs that are equally or more potent that ARTX-2 for advancement to aPhase II project where further PK and toxicity testing will allow us to identify a single compound that will beadvanced into IND-enabling studies.Artus Therapeutics PA-20-260 / PI: Frederick M. Ausubel - Page 1 of 1
Public Health Relevance Statement: First-in-class small molecule therapeutics to enhance gut barrier function in inflammatory bowel disease
PA-20-260, R43 Phase I SBIR
PI: Frederick M. Ausubel
Project Narrative
Inflammatory Bowel Disease (IBD), which affects approximately to 3 million Americans, is characterized by
chronic relapsing inflammation and barrier dysfunction, manifested as enhanced permeability of the intestinal
epithelium caused by a breakdown of tight junction proteins between cells. Because FDA-approved IBD
therapeutics target inflammation rather than barrier dysfunction, there is a current need for an orally available,
non-toxic, non-immunosuppressive IBD therapeutic that directly enhances barrier function and blocks
progression to more severe forms of IBD. Artus Therapeutics is developing IBD therapeutics inspired by a
natural microbiome compound that specifically upregulate the production of tight junction proteins and decrease
gut permeability.
Artus Therapeutics PA-20-260 / PI: Frederick M. Ausubel Project Narrative - Page 1 of 1
Project Terms: Acids ; Oral Administration ; Oral Drug Administration ; intraoral drug delivery ; Adrenal Cortex Hormones ; Corticoids ; Corticosteroids ; Affect ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Bifidobacterium ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Sciences ; Biologic Sciences ; Bioscience ; Life Sciences ; Bone Marrow ; Bone Marrow Reticuloendothelial System ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Cells ; Cell Body ; Pharmaceutical Chemistry ; Medicinal Chemistry ; Pharmaceutic Chemistry ; Colitis ; Ulcerative Colitis ; Ulcerated Colitis ; Disease ; Disorder ; Down-Regulation ; Downregulation ; Enzymes ; Enzyme Gene ; Epithelial Cells ; Exhibits ; Goals ; Human ; Modern Man ; Hydrolysis ; India ; Inflammation ; Inflammatory Bowel Diseases ; Inflammatory Bowel Disorder ; Institutes ; Liver ; hepatic body system ; hepatic organ system ; macrophage ; MÏ ; Mucous Membrane ; Mucosa ; Mucosal Tissue ; Mus ; Mice ; Mice Mammals ; Murine ; Patients ; Permeability ; Drug Kinetics ; Pharmacokinetics ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Production ; Proteins ; Publishing ; Relapse ; Adult Respiratory Distress Syndrome ; ARDS ; Acute Respiratory Distress ; Acute Respiratory Distress Syndrome ; Adult ARDS ; Adult RDS ; Da Nang Lung ; Shock Lung ; Stiff lung ; wet lung ; Rodent ; Rodentia ; Rodents Mammals ; Science ; stem cells ; Progenitor Cells ; Testing ; transcription factor ; Basal Transcription Factor ; Basal transcription factor genes ; General Transcription Factor Gene ; General Transcription Factors ; Transcription Factor Proto-Oncogene ; Transcription factor genes ; Trinitrobenzenesulfonic Acid ; Ulcer ; Ulceration ; Universities ; Up-Regulation ; Upregulation ; Aryl Hydrocarbon Receptor ; 2,3,7,8-Tetrachlorodibenzo-p-dioxin Receptors ; AH Receptors ; Dioxin Receptors ; Nuclear Translocator ; Polyaromatic Hydrocarbon Receptors ; TCDD Receptors ; cytokine ; Sodium Dextran Sulfate ; Mesalamine ; 5-Aminosalicylic Acid ; Asacol ; Mesalazine ; Pentasa ; Rowasa ; m-Aminosalicylic Acid ; meta-Aminosalicylic Acid ; base ; improved ; Acute ; Chronic ; Phase ; Biological ; Series ; Chemicals ; Epithelial ; intestinal epithelium ; Tight Junctions ; Occluding Junctions ; Zonula Occludens ; Toxicity Tests ; Toxicity Testing ; analog ; occludin ; Functional disorder ; Dysfunction ; Physiopathology ; pathophysiology ; Therapeutic ; Inflammatory ; scaffolding ; scaffold ; Immunes ; Immune ; Oral ; 3-D ; 3D ; three dimensional ; 3-Dimensional ; Nuclear ; American ; microbial ; Toxicities ; Toxic effect ; Alcoholic ; Boozer ; Dependent drinker ; problem drinker ; Pathogenesis ; Genetic analyses ; genetic analysis ; (TNF)-α ; Cachectin ; Macrophage-Derived TNF ; Monocyte-Derived TNF ; TNF ; TNF A ; TNF Alpha ; TNF-α ; TNFA ; TNFα ; Tumor Necrosis Factor ; Tumor Necrosis Factor-alpha ; TNF gene ; Gut Epithelium ; gastrointestinal epithelium ; Modeling ; response ; claudin 4 ; Regenerative Medicine ; Dose ; Symptoms ; Data ; Erythroid ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Tissue Model ; Development ; developmental ; Pathway interactions ; pathway ; pre-clinical ; preclinical ; microbiome ; healing ; design ; designing ; non-alcoholic ; nonalcoholic ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; Resistance ; resistant ; mouse model ; murine model ; therapeutic target ; clinical remission ; FDA approved ; efficacy testing ; small molecule therapeutics ; experimental study ; experiment ; experimental research ; efficacy study ; preservation ; lead optimization ; Intestinal permeability ; Gut Epithelial Permeability ; Gut Hyperpermeability ; Gut permeability ; Intestinal Epithelial Permeability ; Intestinal Hyperpermeability ; side effect ; infection risk ; pharmacokinetics and pharmacodynamics ; PK/PD ; dietary ;
