Project Summary/Abstract Recognition of peptide antigens presented by major histocompatibility complexes (MHCs) by T cell receptors is a fundamental molecular mechanism by which T cells sense and respond to foreign antigens such as viral proteins and mutant oncoproteins. Yet many cancer-specific antigens are poorly presented by common MHC alleles, greatly limiting the ability of T cells to be mobilized against patient tumors. Methods to increase the MHC-I presentation of cancer specific oncogenic driver mutations could greatly augment anti-cancer immune responses. Conversely, misrecognition of self-antigens by T cells breaks the immune tolerance and leads to the destruction of healthy tissue, a process that underlies multiple autoimmune diseases. Genetic studies have revealed strong linkages between specific MHC alleles and autoimmune disease risk (e.g. HLA- B*27:05/ankylosing spondylitis, HLA-DQ2/celiac disease and type 1 diabetes), providing a strong rationale to therapeutically target these MHC alleles. Although MHC proteins have not been targeted by small molecule drugs, recent studies on idiosyncratic drug hypersensitivity reactions uncovered the propensity of MHC proteins to accommodate drug-like compounds. Here we seek to exploit this understanding to develop small molecule ligands of MHC proteins for the treatment of cancer and autoimmune diseases. By leveraging a new high throughput assay we have established to monitor compound stabilization of MHC proteins as well as their covalent reactivity, we propose to develop small molecules that 1) enhance the presentation of cancer antigens by MHC Class I proteins via a molecule glue mechanism, 2) block the antigen presentation by autoimmune- associated MHC Class I proteins, and 3) allosterically perturb the function of autoimmune-associated MHC Class II proteins. The proposed research program will deliver novel chemical matter to enable new therapeutic mechanisms for cancer and autoimmune diseases. In addition, the methods we develop here will lay the foundation for the systematic discovery of small molecules that modulate of MHC-mediated antigen presentation.

Project Narrative While T cells provide powerful protection against viral infections and tumors, many cancers evade immune surveillance, and T cell destruction of self-tissues can lead to severe autoimmune diseases. Methods to control T cell reactivity remain scarce. This project will develop small molecules that fine-tune the recognition of antigens by T cells as a new therapeutic approach for the treatment of cancer and autoimmune diseases.