Evaluation and In Situ Library Expansion of Small Molecule MHC-I Inducers

Immunotherapy has emerged as a powerful strategy for combating cancer by harnessing the patient immune system to recognize and eliminate malignant cells. The major histocompatibility complex class I (MHC-I) has a pivotal role in the recognition step. These surface proteins present cancer-specific neoantigens to CD8+ T cells, which triggers activation and T cell-mediated killing. However, cancer cells can often evade immune detection by downregulating MHC-I surface expression, which renders the immune response less effective. In turn, this resistance mechanism offers an opportunity to bolster MHC-I surface expression via therapeutic interventions. Here, we conducted an initial comprehensive evaluation of previously purported small molecule MHC-I inducers and identified heat shock protein 90 (Hsp90) inhibitors as privileged inducers of MHC-I surface expression. With a core scaffold in hand, we employed an in situ click chemistry-based derivatization strategy to generate 380 novel compounds in the same family. New agents from this library showed high levels of induction, with one of the triazole-based analogs, CliMB-325 , also enhancing T cell activation and exhibiting lower toxicity, which could potentiate some immunotherapeutic modalities. Moreover, we demonstrated the potential of a click chemistry-based diversification strategy for the discovery of small molecules to counter immune evasion.