Project Grant R33HL161804

OPTIMIZATION OF FIBROBLAST-SELECTIVE INHIBITORS OF YAP/TAZ AS NOVEL THERAPEUTICS FOR PULMONARY FIBROSIS - PROJECT SUMMARY IDIOPATHIC PULMONARY FIBROSIS IS A CHRONIC, PROGRESSIVE AND CONCLUSIVELY FATAL DISEASE IN WHICH ABERRANT FIBROBLAST PROLIFERATION, CONTRACTION, AND EXTRACELLULAR MATRIX (ECM) DEPOSITION CAUSES LUNG FUNCTION DECLINE. STUDIES BY OUR GROUP AND OTHERS, HAVE IDENTIFIED A PIVOTAL ROLE FOR YES-ASSOCIATED PROTEIN 1 (YAP) AND TRANSCRIPTIONAL COACTIVATOR WITH PDZ-BINDING MOTIF (TAZ) TRANSCRIPTION CO-FACTORS IN ACTIVATING FIBROBLASTS TO DRIVE FIBROSIS IN THE LUNG. ALTHOUGH THESE STUDIES HIGHLIGHT THE YAP/TAZ TRANSCRIPTIONAL PROGRAM AS A POTENTIAL TARGET FOR DRUG DISCOVERY, THE MULTITUDE OF SIGNALING INPUTS MODULATING THIS PATHWAY, YAP AND TAZ UBIQUITOUS EXPRESSION, AND THEIR INVOLVEMENT IN A WIDE ARRAY OF CELL FUNCTIONS, INCLUDING STEM CELL MAINTENANCE, EPITHELIAL AND ENDOTHELIAL HOMEOSTASIS, RENDER THEM CHALLENGING THERAPEUTIC TARGETS. THEREFORE, A TREATMENT STRATEGY TARGETING YAP/TAZ IN FIBROBLASTS SELECTIVELY OVER EPITHELIAL AND ENDOTHELIAL CELLS WOULD PROVIDE A NOVEL AVENUE TO TREAT IPF. WHILE WE HAVE SHOWN THAT FIBROBLAST-SELECTIVE INHIBITION OF NUCLEAR LOCALIZATION OF YAP/TAZ REVERSES FIBROSIS IN IPF MOUSE MODELS USING DOPAMINE RECEPTOR D1 AGONISTS, CHALLENGES IN DEVELOPMENT OF SUCH COMPOUNDS INTO EFFECTIVE THERAPIES HAVE LED US TO PERFORM A TARGET-AGNOSTIC HIGH-THROUGHPUT SCREEN, WHICH IDENTIFIED SEVERAL SELECTIVE SMALL MOLECULE HIT COMPOUNDS WITH VALIDATED ANTI-FIBROTIC ACTIVITY IN CELL-BASED ASSAYS. THE GOAL OF THIS PHASED R61/R33 PROPOSAL IS TO FURTHER CHARACTERIZE AND OPTIMIZE OUR NOVEL FIBROBLAST SELECTIVE YAP/TAZ INHIBITORS INTO POTENT AND SELECTIVE COMPOUNDS WITH VALIDATED ANTI-FIBROTIC ACTIVITY IN VITRO AND EX VIVO, AND WITH FAVORABLE IN VITRO ADME/PK PROPERTIES (R61 PHASE). WE WILL THEN OPTIMIZE DRUG-LIKE IN VIVO PROPERTIES FOR 1-2 LEAD SCAFFOLDS, CONFIRMING THEIR ANTI-FIBROTIC EFFECTS CAUSED BY CELL TYPE-SELECTIVE INHIBITION OF YAP/TAZ IN IN VIVO IPF MOUSE MODELS (R33 PHASE). TOGETHER, THE PROPOSED EXPERIMENTS WILL GENERATE LEAD MOLECULE(S), WHICH CAN SERVE AS THE BASIS FOR AN EFFECTIVE THERAPY TO TREAT IPF PATIENTS.