NOVEL TXNIP DEGRADERS FOR TREATING DIABETES - MORE THAN 30 MILLION AMERICAN HAVE DIABETES (~10% OF THE POPULATION), MAKING IT A MAJOR HEALTH ISSUE. AVAILABLE THERAPIES FOR DIABETICS INCLUDE INSULIN REPLACEMENT OR VARIOUS DRUGS THAT MODULATE INSULIN PRODUCTION/SENSITIVITY OR REDUCE BLOOD SUGAR LEVELS BY OTHER MECHANISMS. FOR MANY PATIENTS, HOWEVER, AVAILABLE TREATMENTS ARE LIMITED BY EFFICACY OR CONVENIENCE/COMPLIANCE ISSUES. THUS, ALTERNATIVE THERAPEUTICS, PARTICULARLY THOSE WITH NOVEL MECHANISMS OF ACTION, ARE NEEDED TO MANAGE DIABETES, EITHER AS SINGLE AGENTS OR COMPONENTS OF COMBINATION REGIMENS. TXNIP (THIOREDOXIN-INTERACTING PROTEIN), A REGULATOR OF VARIOUS ASPECTS OF METABOLISM, HAS EMERGED AS A POTENTIAL DIABETES DRUG TARGET. THIS PROTEIN REGULATES THE CELL'S REDOX STATE AND REPORTEDLY ACTS AS A TUMOR SUPPRESSOR, IN ADDITION TO REGULATING GLUCOSE METABOLISM. NOTABLY, TXNIP KNOCKDOWN LEADS TO ANTI-DIABETIC EFFECTS IN MICE, SO AGENTS THAT INHIBIT TXNIP OR REDUCE ITS CONCENTRATION ARE POTENTIAL THERAPIES FOR DIABETES. PROTEIN CONTENT AND ACTIVITY IN CELLS IS REGULATED LARGELY BY THE UBIQUITIN- PROTEASOME SYSTEM, THROUGH WHICH CONJUGATION AND DECONJUGATION OF UBIQUITIN TO AND FROM TARGET PROTEINS ATTENUATES OR INCREASES CELL CONTENT OR ALTERS THE PROTEIN'S ACTIVITY THROUGH COMPARTMENTATION OR OTHER MEANS. THE HUMAN PROTEOME CONTAINS MORE THAN 600 UBIQUITIN E3 LIGASES (UBIQUITIN-LIGATING ENZYMES), MANY OF WHICH ARE VALIDATED THERAPEUTIC TARGETS FOR DRUG DISCOVERY. TXNIP IS UBIQUITINATED BY THE E3 LIGASE ITCH AND SUBSEQUENTLY DEGRADED IN THE PROTEASOME. ACTIVATION OF ITCH, THEREFORE, IS A PROMISING THERAPEUTIC STRATEGY TO ATTENUATE TXNIP LEVELS, INCREASING GLUCOSE UPTAKE AND DAMPENING THE DIABETIC STATE. THE THERAPEUTIC HYPOTHESIS FOR THE PROPOSED PROJECT IS THAT ITCH IS, IN FACT, A NOVEL TARGET FOR DIABETES THERAPY, AND ACTIVATORS OF ITCH CAN BE FOUND THAT WILL INCREASE TXNIP DEGRADATION IN CELLS AND THEREBY COMBAT DIABETES. THROUGH HIGH THROUGHPUT SCREENING, PROGENRA HAS IDENTIFIED NOVEL SMALL MOLECULE ACTIVATORS OF ITCH, OF WHICH ONE - P76251 - PROVIDED PROOF OF CONCEPT FOR THE THERAPEUTIC HYPOTHESIS BY INDUCING ROBUST TXNIP DEGRADATION IN A HUMAN CELL LINE IN A CONCENTRATION-DEPENDENT MANNER. IN THE FEASIBILITY STUDY PROPOSED HERE, P76251 WILL BE TESTED FOR ITS ABILITY TO DEGRADE TXNIP IN HUMAN PANCREATIC BETA CELLS (INS-1 CELL LINE AND ISOLATED HUMAN ISLETS), AND IN VIVO PROOF OF CONCEPT WILL BE ESTABLISHED FOR P76251 BY ASSESSMENT OF ITS ANTI-DIABETIC EFFECTS IN MICE. IN PHASE II, PRECLINICAL DEVELOPMENT WILL CONTINUE WITH ADDITIONAL EFFICACY STUDIES, CHEMICAL OPTIMIZATION, AND ADME/PK AND TOXICOLOGY STUDIES.