Project Grant R44AR076772

PRECLINICAL DEVELOPMENT OF THE TAK1 INHIBITOR HS-276 FOR THE TREATMENT OF RHEUMATOID ARTHRITIS - PROJECT SUMMARY / ABSTRACT RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE IN WHICH HYPERACTIVATED IMMUNE CELLS INDUCE MALADAPTIVE PERSISTENT INFLAMMATION IN THE JOINTS, LEADING TO SYNOVIAL INFLAMMATION AND BONE REMODELING. IN THE US, RA CURRENTLY AFFECTS ROUGHLY 1% OF THE POPULATION AND CARRIES A TOTAL ANNUAL SOCIETAL COST BURDEN OF APPROXIMATELY $39.2 BILLION. IN RA, SUSTAINED ELEVATIONS OF PRO-INFLAMMATORY CYTOKINES ELICIT CHRONIC TISSUE DAMAGE AND PAIN, WHICH ULTIMATELY LEADS TO LOSS OF MOBILITY AND SIGNIFICANT IMPAIRMENT OF THE PATIENT'S LIFESTYLE. TUMOR NECROSIS FACTOR (TNF) HAS BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN RA PATHOGENESIS AND PRO-INFLAMMATORY SIGNALING, AND VARIOUS TNF-SEQUESTERING ANTIBODIES (E.G., REMICADE AND ENBREL) ARE INDICATED FOR THIS DISEASE. HOWEVER, UP TO 40% OF PATIENTS FAIL TO RESPOND TO THESE THERAPIES, TREATMENTS ARE BURDENED WITH HIGH ADMINISTRATION COSTS AND NONCOMPLIANCE RATES, AND ALMOST ALL CARRY SERIOUS SAFETY ISSUES, LEADING TO A LARGE NEED FOR AN ORALLY BIOAVAILABLE ALTERNATIVE WITH A NOVEL MOA WHICH CAN MODULATE THE INTRACELLULAR EFFECTS OF TNF AND MITIGATE RA SYMPTOMS AND DAMAGE. A KEY SIGNALING ELEMENT IN THE MEDIATED TNF PRO-SURVIVAL/INFLAMMATORY RESPONSE PATHWAY IS THE PROTEIN KINASE TGFSS-ACTIVATED PROTEIN KINASE 1 (TAK1). TAK1 PLAYS A CRUCIAL ROLE IN FACILITATING ACTIVATION OF PROTEIN KINASE-MEDIATED SIGNALING PATHWAYS IMPLICATED IN THE PATHOGENESIS OF INFLAMMATORY AND ONCOGENIC PROCESSES. BECAUSE OF ITS CRITICAL ROLE IN THESE PATHWAYS, TAK1 HAS EMERGED AS A POTENTIAL THERAPEUTIC TARGET FOR THE TREATMENT OF VARIOUS INFLAMMATORY-MEDIATED DISEASES, INCLUDING RA. OUR RECENT DISCOVERY OF THE TAKINIB SCAFFOLD AND SUBSEQUENT MEDICINAL CHEMISTRY EFFORTS HAVE LED TO THE DEVELOPMENT OF AN ORALLY BIOAVAILABLE, HIGHLY SELECTIVE AND POTENT (IC50 ~2.5NM) INHIBITOR OF TAK1, HS-276. THIS LEAD CANDIDATE HAS DEMONSTRATED PROMISING RESULTS FROM PRELIMINARY EFFICACY AND PHARMACOKINETIC STUDIES WHICH SUPPORT TARGETED INHIBITOR OF TAK1 AS A VALID APPROACH TO REGULATING TNF PRODUCTION AND SIGNALING. ADDITIONALLY, SINCE THE ROLE OF TAK1 APPEARS TO BE LARGELY CONFINED TO MEDIATING TNF SIGNALING, SUCH AN ORALLY BIOAVAILABLE DRUG SHOULD POTENTIALLY HAVE LIMITED SIDE EFFECTS, IN CONTRAST TO CURRENT TARGETED RA THERAPEUTICS. IN ORDER TO PROGRESS HS-276 TOWARDS IND-ENABLING SAFETY STUDIES, THIS PROJECT INVOLVES THE FOLLOWING SPECIFIC AIMS: AIM 1: ESTABLISH SAFETY AND CHEMICAL TOXICOLOGY OF HS-276 IN PRE-IND-ENABLING STUDIES. MILESTONE: ESTABLISH ROUTE OF METABOLISM, MAXIMUM TOLERATED DOSES, AND DEFINE UNEXPECTED TOXICITY ISSUES. AIM 2: DEFINE THE THERAPEUTIC WINDOW FOR HS- 276 IN THE CIA MOUSE MODEL OF HUMAN RA. DETERMINATION OF THERAPEUTIC WINDOW, DEMONSTRATION OF IN VIVO TARGET ENGAGEMENT AND CHARACTERIZATION OF BIOMARKERS OF EFFICACY. MILESTONE: THERAPEUTIC WINDOW FULLY DEFINED. AIM 3: DEVELOP A BACKUP SERIES OF ANALOGS SHOWING ORAL BIOAVAILABILITY AND INCREASED POTENCY. MILESTONE: IDENTIFY BACKUP ANALOGS IN THE EVENT OF A LATE STAGE FAILURE OR LACK OF SUFFICIENT EFFICACY IN VIVO. ACHIEVING THE SPECIFIC AIMS ABOVE WILL PROVIDE A MORE BROADLY CHARACTERIZED LEAD COMPOUND, A SERIES OF ADDITIONAL ANALOGS, AND THE NECESSARY DATA FOR US TO PURSUE THE COMMERCIALIZATION READINESS PILOT PROGRAM TO FUND IND-ENABLING STUDIES.