Project Grant R61NS119714

DEVELOPING NONMUSCLE MYOSIN II INHIBITORS FOR THE TREATMENT OF GLIOBLASTOMA - PROJECT SUMMARY AN AREA OF SIGNIFICANT UNMET NEED IS THE TREATMENT OF GLIOBLASTOMA (GBM), AN AGGRESSIVE, FAST-GROWING AND LETHAL BRAIN CANCER THAT REPRESENTS 15% OF ALL BRAIN TUMORS. IF LEFT UNTREATED, GBM IS TYPICALLY FATAL WITHIN THREE MONTHS. AND, DUE TO A HIGH RATE OF RECURRENCE, THE CURRENT STANDARD OF CARE, CONSISTING OF SAFE MAXIMAL TUMOR RESECTION, RADIATION THERAPY AND CHEMOTHERAPY, ONLY EXTENDS SURVIVAL FOLLOWING INITIAL DIAGNOSIS TO ONE YEAR. INVASION AND PROLIFERATION ARE DEFINING PHENOTYPES OF GBM, AND GBM CELLS DO ONLY ONE OR THE OTHER. HOWEVER, BLOCKING INVASION STIMULATES PROLIFERATION AND VICE VERSA, IMPLYING THAT AN IDEAL THERAPEUTIC TARGET MUST SATISFY 2 CRITERIA: 1) DRIVE BOTH INVASION AND PROLIFERATION AND 2) BLOCK BOTH WHEN INHIBITED, EVEN WHEN THEIR PATHWAYS ARE ACTIVE. THROUGH EXTENSIVE GENETIC INTERVENTIONS, NONMUSCLE MYOSIN II (NMII) FAMILY OF MOLECULAR MOTORS HAS BEEN SHOWN TO MEET THESE CRITERIA. HOWEVER, THE TRANSLATIONAL POTENTIAL OF THIS RESEARCH HAS BEEN LIMITED BY THE LACK OF A CLINICALLY SAFE, CNS-PENETRANT NMII SMALL MOLECULE INHIBITOR. FOLLOWING MEDICINAL CHEMISTRY EFFORTS SUPPORTED BY A BLUEPRINT NEUROTHERAPEUTICS (BPN) AWARD, CLINICALLY SAFE DERIVATIVES OF THE SMALL MOLECULE NMII ALLOSTERIC INHIBITOR BLEBBISTATIN ARE UNDER DEVELOPMENT AS A TREATMENT FOR DRUG ADDICTION. DEVELOPMENT OF THIS CLASS OF COMPOUNDS HAS ENABLED PRELIMINARY PROOF-OF-PRINCIPLE STUDIES INDICATING THAT THESE NMII INHIBITORS SIGNIFICANTLY IMPROVE SURVIVAL IN AN AGGRESSIVE MURINE MODEL OF GBM, LIKELY THROUGH THE INHIBITION OF CYTOKINESIS (CELL DIVISION) AND EVENTUAL GBM CELL DEATH. THE OVERARCHING GOAL OF THE CURRENT PROPOSAL IS TO ADVANCE THE POTENTIAL FOR TREATING GBM WITH AN NMII SMALL MOLECULE INHIBITOR BY POSITIONING THE PROGRAM TO BE COMPETITIVE FOR ENTRY INTO THE BPN. THE R61 PHASE (YEAR 1) WILL CONSIST OF [1] SCALE UP OF THE LEAD COMPOUND, SR-561, [2] IN VITRO SCREENING OF GBM CELL LINES TO AID SELECTION OF IN VIVO EFFICACY MURINE MODELS TO BE USED IN THE R33 PHASE AND [3] INITIATION OF MEDICINAL CHEMISTRY TO FURTHER OPTIMIZE SR-561 TO IMPROVE PROPERTIES AIMED AT THE SPECIFIC THERAPEUTIC NEEDS OF A GBM TREATMENT. FOLLOWING SUCCESSFUL ACHIEVEMENT OF THE MILESTONES DETAILED IN THE PROPOSAL, THE R33 PHASE (YEARS 2 AND 3) WILL INVOLVE [1] A CONTINUATION OF COMPOUND OPTIMIZATION BY MEDICINAL CHEMISTRY, [2] IN VIVO EFFICACY TESTING WITH SR-561 AND AN OPTIMIZED ANALOG, [3] IN VITRO AND IN VIVO DMPK PROFILING AND [4] COMPOUND TOLERABILITY TESTING. THE PROPOSED WORK IS EXPECTED TO ESTABLISH THE NECESSARY PARAMETERS FOR SUCCESSFUL ENTRY INTO THE BPN PROGRAM TO ADVANCE AN NMII SMALL MOLECULE INHIBITOR TO THE CLINIC FOR THE TREATMENT OF GBM.