Small Molecule Modulation of MHC-I Surface Expression: A Click Chemistry-Based Discovery Approach

ABSTRACT Immunotherapy has emerged as a powerful strategy for combating cancer by harnessing the patient’s immune system to recognize and eliminate malignant cells. Major histocompatibility complex class I (MHC-I) plays a pivotal role by presenting neoantigens to CD8+ T cells, triggering T cell-mediated killing. However, cancer cells often evade detection by downregulating MHC-I surface expression, hindering the immune response. This resistance mechanism offers an opportunity to bolster MHC-I surface expression via therapeutic interventions. We conducted a comprehensive evaluation of previously purported small molecule MHC-I inducers and identified heat shock protein 90 (Hsp90) inhibitors as privileged enhancers. Using a core scaffold, we employed an in situ click chemistry-based derivatization strategy to generate 380 novel compounds. New agents showed high induction levels, with one triazole-based analog, CliMB-325 , also enhancing T cell activation and exhibiting lower toxicity. Altogether, we demonstrated the potential of click chemistry-based diversification for discovering small molecules to counter immune evasion.