Evaluation and In Situ Library Expansion of Small Molecule MHC-I Inducers
Kelly, J. J.; Newkirk, S. E.; Chordia, M. D.; Pires, M.
Show abstract
Immunotherapy has emerged as a powerful strategy for combating cancer by harnessing the patients 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.
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