JILLION THERAPEUTICS INC.

2025-05-07

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Department of Health and Human Services

SYNERGY BETWEEN ARTIFICIAL INTELLIGENCE AND DNA-ENCODED LIBRARY TECHNOLOGIES TO IDENTIFY POLYPHARMACOLOGICAL THERAPEUTICS FOR SUBSTANCE USE DISORDERS - PROJECT SUMMARY SYNERGY BETWEEN ARTIFICIAL INTELLIGENCE AND DNA-ENCODED LIBRARY TECHNOLOGIES TO IDENTIFY POLYPHARMACOLOGICAL THERAPEUTICS FOR SUBSTANCE USE DISORDERS THE OBJECTIVE OF THIS PHASE I SBIR PROJECT IS TO GENERATE SYNERGY BETWEEN ARTIFICIAL INTELLIGENCE (AI) AND OUR OWN INNOVATIVE AND PROPRIETARY DNA-ENCODED LIBRARY (DEL) DRUG DISCOVERY PLATFORM TO IDENTIFY NOVEL MULTIVALENT COMPOUNDS RELEVANT FOR SUDS. EACH TECHNOLOGY COMPLEMENTS THE OTHER EXTREMELY WELL. THE OVERREACHING GOAL IS TO RESTORE, WITH ONE COMPOUND, COMPLEX BRAIN FUNCTIONS IMPACTING TWO, AND POSSIBLY 3, IMPORTANT PATHWAYS. SUDS, RESULT FROM THE IMBALANCE OF OPIOID AND DOPAMINERGIC PATHWAYS AFFECTING THE REWARD SYSTEM, THE MESOCORTICOLIMBIC DOPAMINERGIC SYSTEM IN PARTICULAR, LEADING TO LONG-LASTING REWIRING OF THE BRAIN, AND INVOLVING THE BRAIN DEFAULT-MODE NETWORK. WE HAVE EXTENSIVELY STUDIED NUMEROUS RELEVANT PATHWAYS, AND THE BASAL GANGLIA SIGNALING IN GENERAL, IN THE GREENGARD LAB. WE WILL IDENTIFY MOLECULES THAT TARGET “2+1” NEUROTRANSMITTER SYSTEMS: 2 IMMUTABLE SYSTEMS ARE THE OPIOID AND DOPAMINERGIC SYSTEMS TO REDUCE CRAVINGS AND WITHDRAW SYMPTOMS WHILE ADDRESSING REWARD; 1 ACCESSORY SYSTEM WILL BE THE SEROTONERGIC SYSTEM TO ADDRESS EMOTIONAL AND PSYCHOLOGICAL ASPECTS OF SUDS. G PROTEIN COUPLED RECEPTORS (GPCRS) CONSTITUTE A CRUCIAL THERAPEUTIC CATEGORY AND OUR PROPOSAL AIMS TO FOCUS ON THE OPIOID RECEPTOR DELTA (OPRD1) AND THE DOPAMINE RECEPTOR D3 (DRD3), WHICH, ACCORDING TO OUR EXPERTISE, EMERGE AS THE STRONGEST DUO CANDIDATE FOR POLYPHARMACOLOGY TO POTENTIALLY RESTORE EQUILIBRIUM TO BASAL GANGLIA SIGNALING, WITHOUT THE DELETERIOUS EFFECTS OF OTHER COMBINATIONS. FOR COMORBIDITIES INCLUDING ALTERED MOOD AND INCREASED ANXIETY, WE PROPOSE TO FOCUS ON THE SEROTONIN RECEPTOR 1A (HTR1A). THE TRADITIONAL HIGH-THROUGHPUT SCREENING (HTS) DRUG DISCOVERY IS HINDERED BY THE REQUIREMENT FOR LARGE QUANTITIES OF PROTEIN TARGET, OFTEN OBTAINED FROM E. COLI AND SYNONYMOUS OF NON-PHYSIOLOGICAL CONDITIONS, HEAVY LOGISTIC AND HIGH COSTS. THE DEL TECHNOLOGY OVERCOME THOSE LIMITATIONS, AND IT LEADS TO LARGE NUMBER OF HITS THAT CAN COME WITH THEIR OWN LIMITATIONS, ESPECIALLY IN THE CONTEXT OF POLYPHARMACOLOGY. AI CAN REPLACE BOTH, BUT IT COMES WITH ITS OWN LIMITATIONS. THE STARTING POINT OF AI STUDIES IS A CRYSTAL STRUCTURE THAT MIGHT MISS DYNAMISM, IF NOT PLAIN ACCURACY. AI GENERATES EXCESSIVELY LARGE NUMBER OF HITS, THAT OFTEN DO NOT EXIST, CANNOT BE MADE OR COME WITH EXORBITANT COSTS. WE ARE CONVINCED THAT COMBINING DEL AND AI IS THE IDEAL SOLUTION TO ALL OF THE ABOVE. DEL IS COST-EFFECTIVE AND IS BASED ON TANGIBLE COMPOUNDS MADE IN 3 STEPS, USING A REAL RECEPTOR THAT CAN REACT TO THE PRESENCE OF CO-FACTOR AND LIGANDS, AND GENERATE LISTS OF HITS PERFECTLY COMPATIBLE FOR AI, TO SEARCH FOR MULTI TARGET DIRECTED LIGANDS (MTDLS). IN AIM 1, WE WILL FOCUS ON DEL SCREENING OF OPRD1 AND DRD3, PRODUCED IN MAMMALIAN CELLS AND PURIFIED USING A STATE-OF-THE-ART, DETERGENT-FREE PROTOCOL. 125 MILLION DEL COMPOUNDS WILL BE USED PLUS AN EXTRA MILLION OF DEL COMPOUNDS SPECIFICALLY DESIGNED FOR GPCRS, AND THE RESULTING MATERIAL SUBMITTED TO NEXT-GENERATION SEQUENCING (NGS). IN-SILICO ANALYSIS OF 4 DATA POINTS WILL REVEAL THE TOP 1,000 PREFERRED HITS FOR EACH RECEPTOR. AIM 2 WILL LEVERAGE AI AND COMPUTER-BASED METHODS TO ADDRESS POLYPHARMACOLOGY AND SELECT COMPOUNDS THAT HAVE THE CAPACITY TO BIND BOTH RECEPTORS BASED ON DOCKING SCORES. A SHORTER LIST OF SUCH MTDLS WILL BE THEN SUBJECTED TO DOCKING ON HTR1A. A MULTI-PARAMETER OPTIMIZATION STEP WILL PRIORITIZE HITS BASED ON ADMET VALUES. AIM 3 WILL INVOLVE THE CHEMICAL SYNTHESIS OF ON-DNA AND OFF-DNA COMPOUNDS. EACH HIT WILL BE VALIDATED FOR BINDING, FOLLOWED BY ACTIVITY ASSESSMENT IN MAMMALIAN CELLS. THE PROGRAM AIMS TO IDENTIFY AND VALIDATE DUAL/TRIPLE COMPOUNDS WITH A KD THE LOW MACROMOLAR RANGE OR LOWER, AND DEMONSTRATE RECEPTOR ACTIVITY. THIS ACHIEVEMENT WILL SERVE AS A ROBUST PROOF OF CONCEPT, FULLY VALIDATING PHASE I AND PROVI

399483.00

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2024-09-20

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Department of Health and Human Services

THE USE OF DNA-ENCODED LIBRARY (DEL) TECHNOLOGY FOR THE IDENTIFICATION OF THERAPEUTIC MOLECULES TO TREAT OPIOID USE DISORDERS (OUDS) - PROJECT SUMMARY THE USE OF DNA-ENCODED LIBRARY (DEL) TECHNOLOGY FOR THE IDENTIFICATION OF THERAPEUTIC MOLECULES TO TREAT OPIOID USE DISORDERS (OUDS). THIS PHASE I SBIR PROJECT AIMS AT THE IDENTIFICATION, USING A NOVEL DEL DRUG DISCOVERY PLATFORM, OF SMALL MOLECULAR WEIGHT COMPOUNDS THAT CAN BIND TO THE RECEPTOR GPR26 BELONGING TO THE FAMILY OF G-PROTEIN COUPLED RECEPTORS (GPCRS) WITH THE GOAL OF RESTORING BRAIN FUNCTIONS ASSOCIATED WITH THE REWARD SYSTEM WITHOUT AFFECTING OPIOID RECEPTORS. EFFECTS OF OPIOIDS ARE MEDIATED THROUGH GPCR Μ-OPIOID RECEPTORS (MORS) AND INDIRECTLY THROUGH DOPAMINERGIC PATHWAYS VIA DOPAMINE RECEPTORS. SOME OF THESE PATHWAYS, AND THE BASAL GANGLIA SIGNALING IN GENERAL, WERE LARGELY DECIPHERED BY US IN THE GREENGARD LAB OVER THE LAST THREE DECADES. MORPHINE PERTURBS THE MESOLIMBIC DOPAMINERGIC SYSTEM WHICH IS TRIGGERED IN CONDITIONS OF DEPENDENCE AND WITHDRAWAL. FURTHERMORE, MORPHINE-DEPENDENCY IS ASSOCIATED WITH ELEVATED CAMP LEVELS, ALTERING BROAD CAMP SIGNALING, IN THE STRIATUM ESPECIALLY. GPCRS REPRESENT ONE OF THE MOST IMPORTANT THERAPEUTIC CLASSES AND MANY OF THEM REMAIN LARGELY UNDERSTUDIED AND WITHOUT A KNOWN LIGAND (CALLED ORPHAN GPCRS OR OGPCRS). WE HAVE IDENTIFIED SEVERAL OGPCRS STRONGLY AND SELECTIVELY EXPRESSED IN BRAIN REGIONS HIGHLY RELEVANT FOR SUBSTANCE USE DISORDERS (SUDS). THOSE REPRESENT A REMARKABLE AND UNEXPLOITED OPPORTUNITY TO COUNTERACT OUDS IN AN INNOVATIVE WAY, AND WITHOUT TARGETING THE OPIOID RECEPTORS DIRECTLY. WE ARE PROPOSING TO FOCUS THIS PROGRAM ON GPR26 THAT APPEARS TO BE THE STRONGEST CANDIDATE, BASED ON OUR KNOWLEDGE AND PRELIMINARY DATA, TO MODIFY CAMP SIGNALING AND POTENTIALLY REBALANCE THE BASAL GANGLIA SIGNALING. GPCRS DRUG DISCOVERY IS HAMPERED BY THE NEED OF LARGE AMOUNTS OF MOSTLY NON-PHYSIOLOGICAL RECEPTOR PROTEIN (E. COLI) FOR HIGH-THROUGHPUT SCREENING (HTS) AND THE NEED FOR A CLEAR BIOLOGICAL ACTIVITY TO PERFORM HTS DRUG SCREENING. OUR RESEARCH STRATEGY IS TO IDENTIFY GPR26 BINDERS ADDRESSING EACH OF THESE LIMITATIONS BY USING A DNA-ENCODED LIBRARY (DEL) SCREENING APPROACH THAT WILL ALLOW SMALL AMOUNTS OF A PHYSIOLOGICAL/HIGH QUALITY TARGET TO BE USED WITH VERY LARGE SCREENING POWER (125 MILLION ENTIRELY NEW AND PROPRIETARY COMPOUNDS) AND A BINDING-BASED ASSAY THAT IS ACTIVITY-INDEPENDENT. THE CENTRAL HYPOTHESIS IS THAT DUE TO THE VERY LARGE NUMBER OF COMPOUNDS AVAILABLE TO BE TESTED AND THE INHERENT DIVERSITY, IT WILL BE POSSIBLE TO IDENTIFY EFFICIENTLY, IN A COST-EFFECTIVE WAY, COMPOUNDS THAT ARE HIGH-AFFINITY BINDERS (PRE-OPTIMIZATION) OF GPR26. DEL SCREENING PROTOCOLS HAVE BEEN GENERATED AND OPTIMIZED FOCUSING ON MINIMIZING THE AMOUNT OF PROTEIN TO BE USED AND ON PURIFYING PROTEIN TARGETS FROM MAMMALIAN CELLS. THESE STEPS WILL ENSURE THAT A PHYSIOLOGICAL GPR26 VERSION IS USED FOR SCREENING PURPOSES AND THAT SCREEN DUPLICATES WILL INCREASE CONFIDENCE AND IMPROVE HITS’ HEURISTIC VALUES DETERMINATION. AIM 1 WILL BE DEDICATED TO DEL SCREENING CAMPAIGNS AND 125 MILLIONS OF DEL COMPOUNDS WILL BE TESTED USING PURIFIED GPR26 OR GPR26 CONTAINING MEMBRANES AS TARGET SOURCE. GPR26 WILL BE EXPRESSED IN MAMMALIAN CELLS, PURIFIED, AND IMMOBILIZED. THIS WILL ALLOW SYNTHESIS AND VALIDATION STEPS PROPOSED IN AIM 2. AIM 1 WILL GENERATE A LIST OF 100 PREFERRED HITS AND WE WILL HELP PRIORITIZE THEM FOR FURTHER VALIDATIONS. AIM 2 WILL INCLUDE CHEMICAL SYNTHESIS OF ON-DNA COMPOUNDS AND 18 HITS OFF-DNA. ALL HITS WILL BE VALIDATED FIRST FOR PHYSICAL BINDING USING TWO DIFFERENT METHODS AND ACTIVITY WILL BE EVALUATED IN MAMMALIAN CELLS. THIS PROGRAM WILL IDENTIFY AND VALIDATE COMPOUNDS WITH 3-DIGIT NANOMOLAR RANGE KD OR LOWER AND DEMONSTRATING RECEPTOR ACTIVITY. THIS WILL REPRESENT A STRONG PROOF OF CONCEPT FULLY VALIDATING PHASE I AND A STRONG STARTING POINT TO INITIATE PHASE II WITH 3-5 COMPOUNDS.

399884.00

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2024-08-23

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Department of Health and Human Services

TARGETING BIOLOGICALLY RELEVANT TAU MONOMERS AND OLIGOMERS USING A NOVEL DEL DRUG DISCOVERY PLATFORM TO TREAT ALZHEIMER’S DISEASE AND TAUOPATHIES - PROJECT SUMMARY TARGETING BIOLOGICALLY RELEVANT TAU MONOMERS AND OLIGOMERS USING A NOVEL DEL DRUG DISCOVERY PLATFORM TO TREAT ALZHEIMER’S DISEASE AND TAUOPATHIES THIS PHASE I SBIR PROJECT AIMS AT THE IDENTIFICATION USING OUR NOVEL DNA-ENCODED LIBRARY (DEL) DRUG DISCOVERY PLATFORM OF SMALL MOLECULAR WEIGHT COMPOUNDS THAT CAN BIND TO THE PROTEIN MONOMERIC AND/OR OLIGOMERIC TAU AND MODIFY ITS BIOLOGY, ULTIMATELY BLOCKING OR REDUCING ITS TOXICITY. A NUMBER OF NEURODEGENERATIVE DISEASES SUCH AS ALZHEIMER’S DISEASE (AD) AND SPORADIC FRONTOTEMPORAL DEMENTIAS (E.G., PICK’S DISEASE), ARE CALLED TAUOPATHIES BECAUSE OF THE ABNORMAL INTRACELLULAR INCLUSIONS HIGHLY ENRICHED IN TAU PROTEIN THAT CHARACTERIZE THEM. THESE INCLUSIONS OR NEUROFIBRILLARY TANGLES (NFTS) ARE BELIEVED TO BE THE RESULT OF PATHOLOGICAL MISFOLDING OF TAU DUE TO HYPERPHOSPHORYLATION AND LEADING TO OLIGOMERIZATION, FIBRILLIZATION AND INVOLVING SPREADING OF SOLUBLE TAU OLIGOMERS. THOSE FACTS TOGETHER WITH THE PROGRESSION WITH AGE OF TAU PATHOLOGY AND THE DIFFICULTY TO TARGET AΒ PEPTIDE OLIGOMERS MAKE THE IDENTIFICATION OF TAU PATHOLOGY INHIBITORS HIGHLY RELEVANT AND URGENTLY NEEDED FOR AD AND ALL TAUOPATHIES IN GENERAL. TAU DRUG DISCOVERY IS HAMPERED BY THE NEED OF LARGE AMOUNTS OF MOSTLY NON-PHYSIOLOGICAL TAU PROTEIN (E. COLI) FOR HIGH-THROUGHPUT SCREENING (HTS), THE NEED TO USE ELABORATED TAU SYSTEMS THAT ARE NOT HTS COMPATIBLE TO RECAPITULATE TAU BIOLOGY, AND THE NEED FOR A CLEAR TAU BIOLOGICAL ACTIVITY TO PERFORM HTS DRUG SCREENING. OUR RESEARCH STRATEGY IS TO REMOVE THOSE LIMITATIONS AND IDENTIFY TAU BINDERS USING A DEL SCREENING APPROACH THAT WILL ALLOW SMALL AMOUNTS OF A PHYSIOLOGICAL/HIGH QUALITY PROTEIN TARGET TO BE USED WITH VERY LARGE SCREENING POWER (125 MILLION ENTIRELY NEW PROPRIETARY COMPOUNDS) AND A BINDING-BASED ASSAY THAT IS ACTIVITY-INDEPENDENT. THE CENTRAL HYPOTHESIS IS THAT DUE TO THE VERY LARGE NUMBER OF COMPOUNDS AVAILABLE TO BE TESTED AND THE INHERENT DIVERSITY, IT WILL BE POSSIBLE TO IDENTIFY EFFICIENTLY, IN A COST- EFFECTIVE WAY, COMPOUNDS THAT ARE HIGH-AFFINITY BINDERS OF TAU OLIGOMERS AND POSSIBLY PROTOFIBRILS. DEL SCREENING PROTOCOLS HAVE BEEN GENERATED AND OPTIMIZED FOCUSING ON MINIMIZING THE AMOUNT OF PROTEIN TAU TO BE USED AND ON PURIFYING TAU FROM MAMMALIAN CELLS. THESE STEPS WILL ENSURE THAT A PHYSIOLOGICAL TAU VERSION IS USED FOR SCREENING AND VALIDATION PURPOSES. SCREEN DUPLICATES USED ARE INCREASING CONFIDENCE AND IMPROVE HITS’ HEURISTIC VALUES DETERMINATION. AIM 1 WILL BE DEDICATED TO FINALIZING DEL SCREENING CAMPAIGNS WITH MONOMERIC TAU. TAU WILL BE EXPRESSED IN MAMMALIAN CELLS, PURIFIED, AGGREGATED, AND IMMOBILIZED ON BEADS. AIM 1 WILL GENERATE A LIST OF 24-36 HITS BINDING TO MONOMERIC TAU AND NOT FOUND FOR OLIGOMERIC TAU; SPECIFICITY WILL BE INVESTIGATED. PHYSICAL BINDING OF ALL CANDIDATE HITS IDENTIFIED (UP TO 100) WILL BE VALIDATED WITH TWO DIFFERENT METHODS. AIM 2 WILL INCLUDE CHEMICAL SYNTHESIS OF 18 ADDITIONAL NEW HITS AND INTERMEDIARIES, STRUCTURE ACTIVITY RELATIONSHIP STUDIES AND IN-SILICO DOCKING. IMPORTANTLY, AIM 2 WILL HELP IDENTIFYING HIT CANDIDATES THAT CAN AFFECT TAU’S BIOLOGY AND ESPECIALLY OLIGOMERIZATION AND SEEDING. ALTOGETHER, THIS PROPOSAL WILL GENERATE 3-5 COMPOUNDS WITH 3-DIGIT NANOMOLAR RANGE KD OR LOWER AND WILL REPRESENT A STRONG PROOF OF CONCEPT FULLY VALIDATING PHASE I AND A ROBUST STARTING POINT TO INITIATE PHASE II.

496373.00

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