Improving the Oral Bioavailability and In vivo Efficacy of a Novel TAK1 Inhibitor Targeting Rheumatoid Arthritis

Project SummaryAbstract Rheumatoid arthritisRAis a chronic inflammatory disease in which hyperactivated immune cells induce maladaptive persistent inflammation in the jointsleading to synovial inflammation and bone remodelingIn the USRA currently affects roughlyof the population and carries a total annual societal cost burden of approximately $billionIn RAsustained elevations of pro inflammatory cytokines elicit chronic tissue damage and painwhich ultimately leads to loss of mobility and significant impairment of the patient s lifestyleTumor necrosis factorTNFhas been shown to play an important role in RA pathogenesis and pro inflammatory signalingand various TNF sequestering antibodiese gRemicadeand Enbrelare indicated for this diseaseHoweverup toof patients fail to respond to these therapiestreatments are burdened with high administration costs and noncompliance ratesand almost all carry serious safety issuesleading to a large need for an orally bioavailable alternative with a novel MOA which can reduce the intracellular effects of TNF and mitigate RA symptoms and damageA key signaling element in the mediated TNF pro survival inflammatory response pathway is the protein kinase TAKTGFactivated protein kinaseTAKplays a crucial role in facilitating activation of protein kinase mediated signaling pathways implicated in the pathogenesis of inflammatory and oncogenic processesBecause of its critical role in these pathwaysTAKhas emerged as a potential therapeutic target for the treatment of various inflammatory mediated diseases including RAOur recent discovery of the takinib scaffold has identified a highly specific potent inhibitor of TAKICnMand promising results from preliminary efficacy studies have supported targeted inhibition of TAKas a valid approach to regulating TNF production and signalingAdditionallysince the role of TAKappears to be largely confined to mediating TNF signalingsuch an orally bioavailable drug would potentially have limited side effectsin contrast to alternative therapeutics including conventional DMARDsbiologicsand the cutting edge JAK STAT inhibitorse gtofacitinibIn order to successfully attain proof of concept for takinibthe project includes two Specific AimsAimAchieve Oral BioavailabilityBased on the co crystal structure of takinibdevelop a new series of analogs that retain selectivity towards TAKin vitroand are orally bioavailable in normal ratsMilestoneIdentify at leastselective analogs that exhibit significant oral bioavailability in serumAimEfficacy vs EnbrelEvaluate the anti inflammatory response conferred by prioritized lead molecules in the collagen induced arthritisCIAmouse model of RAMilestoneDemonstrate that the lead molecule exhibits equal or better efficacy than Enbrelin the CIA mouse modelAchieving the Specific Aims above will provide for an orally bioavailablefirst in class TAKinhibitor lead compound as an alternative to TNF targeting biologics and JAK STAT inhibitors for treating RACompletion of these studies will provide the necessary data for us to pursue a Phase II NIH SBIR application to fund IND enabling safety studies en route to a Phase I clinical trial Project Narrative Development of an orally bioavailable inhibitor of the protein kinase TAKshould have a major impact on RA treatment strategies by broadening the landscape of therapeutic options for RA patientsCurrent therapies suffer from high response failures and serious safety issueswhich leads to an increased burden on the quality of life of patients and higher costs to the US healthcare system at largeProviding the RA treatment market with a novel alternative to current therapiessuch as a TAKinhibitorwhich is safer and equally or more effective than current productswill significantly improve the quality of care for RA patients in the US and across the globe