Project Grant R41DK136371

SPNS2 INHIBITORS AS RENAL FIBROSIS THERAPY - FIBROSIS IS AN ABERRANT WOUND HEALING PROCESS CHARACTERIZED BY PROGRESSIVE ACCUMULATION OF EXTRACELLULAR MATRIX THAT ULTIMATELY DESTROYS ORGAN FUNCTION. PROGRESSIVE FIBROSIS IS INHERENT TO CHRONIC KIDNEY DISEASE (CKD), WHICH OFTEN LEADS TO END-STAGE RENAL DISEASE. ALTHOUGH PATIENTS CAN BE MAINTAINED BY HEMODIALYSIS WHILE AWAITING TRANSPLANTATION, THEIR'S AND THEIR CARE-GIVER'S QUALITY OF LIFE ARE SIGNIFICANTLY DEGRADED. FURTHERMORE, THE COSTS INCURRED BY THE NATION'S HEALTH SYSTEM ARE ENORMOUS. AN IDEAL MEDICINE WOULD REVERSE FIBROSIS AND RE- ESTABLISH PRISTINE KIDNEY FUNCTION, BUT EVEN THE MORE MODEST GOAL OF SLOWING FIBROTIC PROGRESSION (AND THEREBY DELAYING THE NEED FOR HEMODIALYSIS OR TRANSPLANT) REMAINS BEYOND THERAPEUTIC REACH. THUS, NEW STRATEGIES FOR DEVELOPING EXPERIMENTAL THERAPIES ARE NEEDED. RECENT STUDIES INDICATED THAT LOCAL SPHINGOSINE 1-PHOSPHATE (S1P) SIGNALING IN KIDNEY PERICYTES ENHANCES THE INFLAMMATORY RESPONSE BY RECRUITING CYTOKINES AND CHEMOKINES ON ACTIVATION OF S1P1 RECEPTOR. THE RESULTING INFLAMMATORY CASCADE PROMOTES FIBROSIS. THUS, INTERDICTING AT THE POINT OF SYNTHESIS AND TRANSPORT OF S1P OR ANTAGONISM OF S1P1 RECEPTOR CAN AMELIORATE THE RESULTANT FIBROSIS. THE SOLUTE S1P TRANSPORTER SPNS2 IS RESPONSIBLE FOR THE EXTRACELLULAR RELEASE OF S1P IN PERICYTES (BUT NOT KIDNEY TUBULAR EPITHELIAL CELLS). THE S1P EXPORT INHIBITORS CAN REDUCE INFLAMMATION AND FIBROSIS. INDEED, IN MOUSE MODELS OF KIDNEY FIBROSIS (UNILATERAL ISCHEMIA/REPERFUSION INJURY AND FOLIC ACID TOXICITY), GENETIC DELETION OF SPNS2 OR INHIBITION WITH SMALL MOLECULES SIGNIFICANTLY REDUCED RENAL FIBROSIS AS COMPARED TO CONTROL ANIMALS. TAKEN TOGETHER, THE STRONG PRELIMINARY EVIDENCE SUGGESTS THAT SPNS2 INHIBITORS COULD BE THERAPEUTICALLY USEFUL ANTI-FIBROTIC AGENTS. FLUX THERAPEUTICS HAS THE FIRST-IN CLASS SPNS2 INHIBITORS REPORTED AND IS APPARENTLY THE ONLY TEAM WITH SUCH INHIBITORS, WHICH UNIQUELY POSITIONS THE COMPANY TO MOVE SPNS2 INHIBITORS TOWARDS THE CLINIC. TO ACHIEVE THIS GOAL, WE WILL WINNOW THE THREE BEST COMPOUNDS FROM THREE DIFFERENT SCAFFOLDS THROUGH RIGOROUS ADME-TOX, COUNTER SCREEN, AND PHARMACOKINETIC STUDIES TO IDENTIFY A LEAD COMPOUND IN AIM 1. IN AIM 2, THE LEAD SPNS2 INHIBITOR WILL BE VALIDATED FOR EFFICACY IN THREE DIFFERENT MOUSE MODELS OF KIDNEY FIBROSIS. THIS PROGRAM WILL AFFORD A DRUG-LIKE COMPOUND THAT VALIDATES SPNS2 AS AN ANTI-FIBROTIC DRUG TARGET.