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

## TL;DR

This paper explores using small molecules to boost MHC-I expression on cancer cells, enhancing immune detection and reducing evasion.

## Contribution

A click chemistry-based approach generated novel MHC-I inducers, including a low-toxicity triazole compound that activates T cells.

## Key findings

- Heat shock protein 90 inhibitors were identified as effective MHC-I enhancers.
- Click chemistry produced 380 new compounds, with CliMB-325 showing strong MHC-I induction and T cell activation.
- The method demonstrates potential for discovering small molecules to counter immune evasion in cancer.

## 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 the 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 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 analogue, 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.