Project Grant R00GM159057

INDUCED-PROXIMITY PLATFORM TO CONTROL CELLULAR SIGNALING AND PROTEOSTASIS - THE DEVELOPMENT OF SMALL-MOLECULE MEDICINES THAT INHIBIT DISEASE-CAUSING PROTEINS HAS FUNDAMENTALLY TRANS-FORMED MODERN HEALTHCARE. HOWEVER, CONVENTIONAL DRUGS REQUIRE BINDING TO SPECIFIC ACTIVE POCKETS TO BLOCK PRO-TEIN FUNCTION, A MECHANISM THAT LIMITS THEIR EFFICACY TO ONLY ABOUT 10-15% OF THE HUMAN PROTEOME. MOST DISEASE-RELEVANT PROTEINS LACK THESE ACTIVE SITES, RENDERING THEM UNDRUGGABLE BY TRADITIONAL METHODS. TO OVERCOME THIS BARRIER, THE EMERGING FIELD OF EVENT-DRIVEN PHARMACOLOGY USES SPECIALIZED MOLECULES (SUCH AS PROTACS) TO RECRUIT THE CELL'S NATURAL DISPOSAL MACHINERY TO DEGRADE DISEASE-CAUSING PROTEINS RATHER THAN MERELY INHIBITING THEM. WHILE PROMISING, CURRENT EVENT-DRIVEN APPROACHES FACE MAJOR BOTTLENECKS, INCLUDING DIFFICULTY IDENTIFYING COMPATIBLE MOLECULAR BINDERS AND THE RAPID EMERGENCE OF CELLULAR RESISTANCE TO TREATMENT. THIS RESEARCH PROJECT AIMS TO FURTHER EXPAND EVENT-DRIVEN PHARMACOLOGY BY DEVELOPING TWO INNOVATIVE PLATFORMS THAT OVERCOME THESE LIMITATIONS. FIRST, THE PROJECT LEVERAGES A NOVEL GROUP-TRANSFER PLATFORM TO RAPIDLY CONVERT EXISTING, READILY AVAILABLE PROTEIN INHIBITORS INTO EFFECTIVE TARGETING COMPONENTS. THIS ELIMINATES THE NEED FOR EXPENSIVE, TIME-CONSUMING DISCOVERY CAMPAIGNS AND EXPANDS THE RANGE OF CELLULAR ENZYMES THAT CAN BE HAR-NESSED FOR THERAPEUTIC INTERVENTION. SECOND, WE INTRODUCE A NEW CLASS OF DEGRADERS THAT BYPASS STANDARD CELLULAR MACHINERY, WHICH IS PRONE TO RESISTANCE, AND INSTEAD DIRECTLY RECRUIT INDISPENSABLE CELLULAR PROCESSING UNITS TO DESTROY TARGET PROTEINS. BY EVALUATING THESE NEW THERAPEUTIC MODALITIES AGAINST HIGH-VALUE BIOMEDICAL TARGETS, THIS WORK WILL PROVIDE A SYSTEMATIC FRAMEWORK FOR UNDERSTANDING AND COMBATING DRUG RESISTANCE. ULTIMATELY, THIS RESEARCH WILL PROVIDE DEEP MECHANISTIC INSIGHTS INTO CELLULAR ENGINEERING AND PAVE THE WAY FOR A NEW GENERATION OF HIGHLY EFFECTIVE, RESISTANCE-RESILIENT THERAPEUTICS FOR PREVIOUSLY UNTREATABLE DISEASES.