Project Grant R41AI167105

DEVELOPMENT OF THE HC2099 SERIES OF MMPL3 INHIBITORS TO TREAT TUBERCULOSIS - TARN BIOSCIENCES, INC. IS A START-UP PHARMACEUTICAL COMPANY HEADQUARTERED IN EAST LANSING, MICHIGAN. THE COMPANY IS DEVELOPING NEW THERAPIES FOR TUBERCULOSIS (TB). THE GOAL OF THIS STTR IS TO DEVELOP THE MMPL3 INHIBITOR, HC2099, AS A NEW TREATMENT FOR DRUG SUSCEPTIBLE AND MULTIDRUG-RESISTANT TB (MDR-TB). IN 2019, 10 MILLION PEOPLE WORLDWIDE FELL ILL TO TB WITH ~ 1.4 MILLION LIVES LOST. STANDARD-OF-CARE (SOC) TREATMENT FOR TB CALLS FOR A PROTRACTED 6-MONTH COURSE OF COMBINATION THERAPY TO IN WHICH 14-24% OF PATIENTS ARE NONADHERENT TO THERAPY. THIS LONG DURATION OF TREATMENT, HIGH PILL BURDEN, AND ASSOCIATED ADVERSE DRUG EFFECTS, DRAMATICALLY IMPACTS PATIENT COMPLIANCE AND THE EVOLUTION AND SPREAD OF MDR-TB, WITH ~500,000 NEW MDR-TB INFECTIONS IN 2019. GIVEN THAT RESISTANCE TO SOC TREATMENT IS AS HIGH AS 10% IN MANY COUNTRIES, NEW DRUG REGIMENS, WITH NEW AGENTS ARE REQUIRED FOR SLOWING THE SPREAD OF DRUG RESISTANCE. MYCOBACTERIUM TUBERCULOSIS (MTB) IS A REMARKABLY SUCCESSFUL, IN PART, DUE TO THE COMPLEX CELL ENVELOPE THAT SURROUNDS THE BACTERIUM. MMPL3 IS A MYCOLATE FLIPPASE THAT MOVES THE GLYCOLIPID TREHALOSE MONOMYCOLATE (TMM) TO THE PSEUDOPERIPLASMIC SPACE, FROM WHERE TMM IS MODIFIED TO TREHALOSE DIMYCOLATE (TDM) AND INCORPORATED INTO THE MYCOMEMBRANE. MTB AND M. SMEGMATIS MMPL3 KNOCKDOWN STRAINS SHOW THAT MMPL3 IS ESSENTIAL FOR SURVIVAL BOTH IN VITRO AND IN MICE. MULTIPLE MMPL3 INHIBITORS ALSO EXHIBIT SYNERGISTIC INTERACTIONS WITH TB ANTIBIOTICS, FURTHER SUPPORTING INTEREST IN THIS TARGET. USING AN INNOVATIVE COMBINATION OF UNTARGETED AND TARGETED MUTANT SCREENS, WE HAVE IDENTIFIED TEN NEW AND DISTINCT SCAFFOLDS THAT INHIBIT MMPL3 FUNCTION. ONE OF THESE COMPOUNDS, HC2099, WAS CHOSEN FOR OPTIMIZATION AND CHARACTERIZATION STUDIES GIVEN OBSERVED PROPERTIES USUALLY REGARDED USEFUL FOR DRUGS, INCLUDING HIGH AQUEOUS SOLUBILITY AND STABILITY IN MICROSOMES. STRUCTURE-ACTIVITY-RELATIONSHIP STUDIES INCLUDING THE SYNTHESIS OF >60 ANALOGS RESULTED IN >70-FOLD IMPROVEMENT OF POTENCY. PILOT STUDIES SHOW ONE OF THE OPTIMIZED ANALOGS, MSU- 43085, ACCUMULATES IN MOUSE PLASMA AND LUNGS AND REDUCES MTB GROWTH IN VIVO WHEN ORALLY DELIVERED. THE PRODUCT OF THIS STTR IS HC2099 ANALOGS, A NEW SERIES OF MMPL3 INHIBITORS. HC2099 ANALOGS ARE POTENT (~100 NM EC50), SOLUBLE, ORALLY BIOAVAILABLE INHIBITORS TARGETING A PATHWAY ESSENTIAL FOR MTB SURVIVAL. THE GOAL OF THIS PHASE I PROJECT IS TO PRIORITIZE THREE HC2099 ANALOGS WITH FAVORABLE IN VITRO AND IN VIVO DRUG-LIKE PROPERTIES AND DEMONSTRATE EFFICACY IN CHRONICALLY INFECTED MICE. MEDICINAL CHEMISTRY OPTIMIZATIONS OF HC2099 SERIES WILL BE CONDUCTED TO DEVELOP IMPROVED ANALOGS (AIM 1.1) AND IN VITRO DRUG-LIKE PROPERTIES WILL BE CHARACTERIZED TO BIAS DEVELOPMENT TOWARDS A DRUG-LIKE MOLECULES (AIM 1.2). TO DRIVE TOWARDS PROOF-OF-CONCEPT EFFICACY IN VIVO, FORMULATION STUDIES (AIM 2.1), PK STUDIES (AIM 2.2) AND IN VIVO EFFICACY STUDIES WILL BE CONDUCTED IN TWO MODELS OF MURINE TB INFECTION (AIM 2.3). THE EXPECTED OUTCOME OF THIS WORK IS A PRIORITIZED, ORALLY BIOAVAILABLE HC2099 ANALOG WITH IN VIVO ACTIVITY COMPARABLE TO STANDARD OF CARE ANTIBIOTICS.