Developing small molecule inhibitors of TLR for treatment of rheumatoid arthritis

DESCRIPTION provided by applicant Autoimmune diseases like rheumatoid arthritis RA develop when the immune response targets self antigens leading to inflammation and tissue destruction There is now considerable evidence that recognition of self nucleic acids through toll like receptors TLRs can contribute significantly to sterile inflammation and autoimmunity with the clearest example being the role played by TLR and TLR in the pathogenesis of systemic lupus erythematosus SLE Similarly TLR a potent stimulator of inflammatory cytokines such as IL and TNF has a strong association with RA and other autoimmune indications However the lack of useful animal models a consequence of the different ligand specificity of human TLR and its rodent orthologs has proven to be a major limitation in the study of TLR function and the identification of possible therapeutics We have developed new tools including in vivo animal models that have allowed us to better understand the biology of TLR in autoimmunity and specifically for a role of TLR signaling in RA We propose to use these tools to identify a lead small molecule antagonist for developing a therapeutic for TLR mediated autoimmunity The key objective of this Phase II proposal is to identify lead small molecule antagonists of human TLR from a set of candidate hits that we have identified through high throughput screening with funding from a Phase I SBIR The principal activities will include Advancing hits and identifying lead compounds with specific and improved huTLR antagonist activity through a process of iterative computer aided drug design with structure based modeling and cell based activity Determining the activity of the lead candidates in TLR dependent RA mouse model Conducting preliminary toxicology of lead compounds to support IND enabling studies If successful we anticipate obtaining a small number of lead small molecule candidates that inhibit TLR and have sufficient attributes e g potency to move into IND enabling studies PUBLIC HEALTH RELEVANCE There are drugs that have proven clinically beneficial for the treatment of rheumatoid arthritis RA but these treatments are not effective in all patients and are not without serious side effects This work attempts to develop a drug against a new target human Toll Like Receptor that has been demonstrated to be involved with a variety of autoimmune diseases including RA Our initial efforts have been successful in identifying potential candidates that inhibit this target and the work in this proposal will optimize those candidates and test for anti rheumatic activity in animal models to allow us to move into the clinic