Direct chemical targeting of MHC proteins for the treatment of cancer and autoimmune diseases

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.