Project Grant R43NS119087

EVALUATING THE BLOOD-BRAIN BARRIER BIOAVAILABILITY AND IN VIVO EFFICACY POTENTIAL OF A NOVEL TAK1 INHIBITOR TARGETING CHRONIC PAIN - PROJECT SUMMARY / ABSTRACT CHRONIC PAIN IS A PREVALENT HEALTH CONCERN, AFFECTING UP TO 100 MILLION PEOPLE AND CARRYING AN ECONOMIC BURDEN UP TO $560 BILLION ANNUALLY IN THE US ALONE, YET TREATMENT OPTIONS REMAIN LIMITED. OVER-THE-COUNTER NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) ARE SHORT-ACTING AND FAIL TO ALLEVIATE SEVERE CHRONIC PAIN, AND THESE CONVENTIONAL DRUGS CARRY SERIOUS SAFETY CONCERNS REGARDING GASTROINTESTINAL EVENTS. IN ADDITION, THE NEWER AND MORE SELECTIVE COX-2 INHIBITORS SUCH AS CELEBREX/CELECOXIB AND VIOXX CARRY FDA BOXED WARNINGS CONCERNING SERIOUS RISKS OF HEART ATTACK AND STROKE. SIMILARLY, LONGER-ACTING CENTRALLY-TARGETED THERAPIES SUCH AS OPIOIDS ALSO HAVE POOR EFFICACY AND PRODUCE SERIOUS SIDE-EFFECTS REGARDING ALTERED MENTAL STATE, ADDICTION, AND RESPIRATORY DEPRESSION. THUS, THERE IS A SERIOUS UNMET NEED FOR ALTERNATIVES TO CURRENT TREATMENT OPTIONS FOR PATIENTS SUFFERING WITH CHRONIC PAIN. ONE OF THE MAIN DRIVERS OF CHRONIC PAIN IS INFLAMMATION FOLLOWING TISSUE INJURY OR NERVE INJURY CAUSED BY INCREASED LEVELS OF CYTOKINES SUCH AS TUMOR NECROSIS FACTOR A (TNF), AND A POSITIVE CORRELATION EXISTS BETWEEN TNF LEVELS AND PAIN INTENSITY. TNF CAN BIND TO ITS TNFR1 RECEPTOR LOCATED ON THE TERMINALS OF PRIMARY AFFERENT NOCICEPTORS TO DIRECTLY INCREASE THEIR ACTIVITY, AND CAN ALSO STIMULATE PRO-INFLAMMATORY CYTOKINE PRODUCTION AND IMMUNE CELL ACTIVATION. OUR PRECLINICAL WORK HAS IDENTIFIED TGFSS-ACTIVATED KINASE 1 (TAK1), A KEY SIGNALING ELEMENT IN THE MEDIATED TNF PRO-SURVIVAL/INFLAMMATORY RESPONSE PATHWAY. TAK1 PLAYS A CRUCIAL ROLE IN FACILITATING ACTIVATION OF PROTEIN KINASE-MEDIATED SIGNALING PATHWAYS IMPLICATED IN THE PATHOGENESIS OF CHRONIC PAIN PROCESSES, AND AS A RESULT HAS EMERGED AS A NOVEL TARGET FOR REGULATING CHRONIC PAIN AND INFLAMMATION LINKED TO ENHANCED TNF SIGNALING. OUR RECENT DISCOVERY OF THE TAKINIB SCAFFOLD HAS IDENTIFIED A HIGHLY SELECTIVE, POTENT (IC50 ~2.5NM), AND ORALLY BIOAVAILABLE SMALL MOLECULE INHIBITOR OF TAK1 (TAKINIB ANALOG HS-276). PRECLINICAL STUDIES HAVE DEMONSTRATED THAT TAK1 INHIBITION WITH PARENT TAKINIB PRODUCES A 9-FOLD REDUCTION IN TNF LEVELS ALONGSIDE REDUCED LEVELS OF OTHER CYTOKINES AND CHEMOKINES INVOLVED IN PRO-INFLAMMATORY RESPONSES. ALSO, TAK1 INHIBITION WITH PARENT TAKINIB PREVENTED MECHANICAL AND THERMAL HEAT PAIN, PAIN-RELATED DEPRESSIVE BEHAVIOR, AND EDEMA IN A MODEL OF INFLAMMATORY PAIN. FURTHERMORE, PARENT TAKINIB TREATMENT IN THIS MODEL REDUCED PRO-INFLAMMATORY CYTOKINE AND CHEMOKINE PROTEIN EXPRESSION. IN ORDER TO SUCCESSFULLY ATTAIN PROOF-OF-CONCEPT FOR TAKINIB ANALOG HS-276, THIS PROJECT INCLUDES THREE SPECIFIC AIMS: AIM 1 - EVALUATE THE PHARMACOKINETICS OF HS-276 REGARDING BLOOD-BRAIN BARRIER (BBB) BIOAVAILABILITY. AIM 2 - DETERMINE THE ESTABLISHED (THERAPEUTIC) ANALGESIC POTENTIAL OF HS-276 IN A MONOSODIUM URATE-INDUCED ARTHRITIS MOUSE MODEL OF INFLAMMATORY PAIN EVIDENCED BY REDUCTION IN MECHANICAL AND THERMAL PAIN, AS WELL AS INFLAMMATORY CYTOKINES. AIM 3 - DETERMINE THE THERAPEUTIC ANALGESIC POTENTIAL OF HS-276 IN A STREPTOZOTOCIN-INDUCED MOUSE MODEL OF DIABETIC NEUROPATHY. ACHIEVING THE SPECIFIC AIMS ABOVE WILL PROVIDE WILL PROVIDE THE NECESSARY DATA FOR US TO PURSUE A PHASE II NIH SBIR APPLICATION TO FUND IND-ENABLING SAFETY STUDIES EN ROUTE TO A PHASE I CLINICAL TRIAL.