STING Inhibitor Discovery for Rare and Common Autoimmune Diseases

Principal Investigators for Small BusinessDiscoveryBioMedIncDBMand Nitor TherapeuticsIncNitorProject Summary Abstract The over arching commercial goal for this Nitor TherapeuticsIncNitorand DiscoveryBioMedIncDBMcollaboration is to discover and validate Stimulator of Interferon Genes orSTINGinhibitor ligands in a novel high throughput screeningHTSand validation based Critical Path of bioassaysAberrant activation of the STING pathway by self DNA andgain of functionmutations in the STING protein dimer can lead to autoimmune diseaseThereforewe hypothesize that STING inhibitory ligands may be a promising new strategy for the treatment of autoimmune and inflammatory diseases in which suppression of the type I IFN pathway may show therapeutic benefitThe Nitor and DBM collaboration has designed a Critical Path of cellbased bioassays with HTS and validation bioassay steps so as to discover STING inhibitor ligands from a de novo screen of a diverse small molecule library derived fromdifferent commercial vendors and from a targeted screen of nucleosides nucleotides from our collaborators at TheraChemPreliminary data is presented from a pilot screen of approximatelycompounds and from early validation steps scripted within our Critical PathMilestonefocuses on optimizing and cementing our STING Inhibitor HTS and Validation Critical PathLater efforts in Milestonewill validate these STING inhibitors on additional reporter cell lines with more physiological relevancea THPmonocytic cell line stably expressing the STING reporterand on more relevant diseased human PBMCs isolated from lupus patientsOur validated STING inhibitor ligands will be evaluated by assessing the effect of the inhibitor ligand on the production and secretion of interferonIFNand other secreted inflammatory mediators in response to cGAMPMilestonewill focus on the full HTS campaign to discover and validate novel small molecule STING inhibitorsChemoinformatics analysis of the validated hits will be performed throughout the HTS campaign so as to identify emerging hit chemical series rapidlyWe will then re profilebest in classsmall molecules from each chemical series of family where a common scaffold has been identifiedPhaseSBIR driven work is envisioned where STING inhibitor ligand chemical series where medicinal and formulation chemistry optimization is performed on the best hit to lead chemical serieswhere in vitro ADME and in vivo PK PD are performedand where in vivo proof of concept studies are performed in lupus animal models and mouse models of interferonapathies with key lead small moleculesPHSRevre issuedPage Continuation Format PagePrincipal Investigators for Small BusinessDiscoveryBioMedIncDBMand Nitor TherapeuticsIncNitorPublic Health Relevance Statement Autoimmune diseases are syndromes or disorders in which the body inappropriately targets its own organstissues or cells as being foreign ornon selfDiscoveryBioMedIncDBMand Nitor TherapeuticsNitorare focused on discovering novelStimulator of Interferon GenesorSTINGinhibitors for autoimmune diseasesAmong these autoimmune orautoinflammatorydiseasesit has become apparent that a recently discovered modulatory protein in immunity signaling calledStimulator of Interferon GenesorSTINGis affected directly or indirectlyThe most common autoimmune disease isLupusknown formally as systemic lupus erythematosus or SLEThere is no cure for SLEand it is mainly treated with medicines that suppress the immune system with the aim of keeping symptoms under controlThese medicines have many debilitating side effectsAs suchthe ultimate goal and unmet clinical need is to discover and develop a more focused therapeutic for theLupus umbrella of diseasesLupus falls under the mandate of the NIAID at the NIH and is a focus of Nitor TherapeuticsIn additionwe are focused on more specific rare or niche autoimmune diseases within the Lupus umbrellaDBM is interested particularly in Respiratory and Renal Diseases therapeutic areasImportantlygain of function mutations in the STING gene cause early onset lung vasculopathy and pulmonary inflammation in human patientsnow categorized asSAVIorSTING associated vasculopathy with onset in infancyThese newly categorized diseases are hyperinflammatory in nature and affect mainly the lungblood vessels within the lung and the skinPatients with SAVI can also develop widespread lung damage that leads to pulmonary fibrosis and difficulty in breathingThe SAVI diseases fall under the NHLBI missionGain offunction mutations in the gene encoding STING render the protein constitutively active or more sensitive to stimulation by cGAMPwhich results in elevated production of interferons by a variety of cellsThere are also other rare autoimmune disorders and syndromes that display a prominent interferon response gene signature that may be treated with a STING inhibitorOf importance to DBMSTING inhibitors may also be beneficial in the treatment of lupus nephritisLNLN falls under the mission of the NIDDKAs suchNitor TherapeuticsIncand DiscoveryBioMedInchave formed a synergistic collaboration so as to discover novel and innovative STING inhibitor ligands from a high throughput screening program using intactliving reporter cell linesWe will validate these inhibitors on primary leukocytesPBMCsisolated from Lupus patients monitoring for potential therapeutic effects in vitroThe ultimate commercial goal is to develop orally bioavailable and or inhaled small molecule STING inhibitors for common and rare autoimmune diseasesPHSRevre issuedPage Continuation Format Page