UMIP-54 Small-Molecule Costimulatory Modulation

Problem: Costimulatoryinteractions among receptor-ligand pairs of the TNF superfamily, such as theCD40–CD40L, BAFF-R–BAFF, OX40–OX40L, or RANK–RANKL protein-proteininteractions, play important roles in the activation of immune responsesmediated by T- and B-cells. They represent important therapeutic targets forvarious immune and inflammatory diseases, and several biologics targeting themare either in clinical development or already approved for clinical use. However,biologics can be hindered by several drawbacks, such as immune side effects,complicated development, and lack of oral bioavailability, which can be circumventedby a small molecule option. Hence, we focused on developing small-molecule newchemical entities (NCEs) as possible alternatives to antibody-based biologics,especially as during the last decade such NCEs have been found to be effectivefor some protein-protein interactions and the first two have received FDAapproval for clinical use (venetoclax, lifitegrast), but none are yet availablefor costimulatory interactions. Technology: Researchers at the University of Miami have developed novel small-molecule chemical entities(NCEs) capable of modulating such interactions and confirmed their activity forthe corresponding inflammatory and immune responses in a number of preclinicalmodels. These compounds can be used for therapeutic interventions in diseasesand disorders related to immune or inflammatory responses including autoimmunediseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus(SLE), multiple sclerosis (MS), type I (juvenile) diabetes (T1D), mixedconnective tissue disease (MCTD), celiac disease, Crohn’s disease, Grave’sdisease, Sjögren’s syndrome, dermatomyositis, psoriasis, neurodegenerativedisorders, and others, as well as for immune suppression or tolerance inductionin recipients of organ or cell transplant in general and recipients ofpancreatic islet transplant in particular. Peter Gutenberg pxg372@miami.edu 305-243-4604

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