Small molecule modulators of TOX protein re-invigorate T cell activity

Wu, Bocheng, Chang, Heng Jui, Singh, Prashant, Hostetler, Alexander, Xiang, Yichen, Guo, Shenghao, Wang, Fiona Yihan, Zhong, Julia J, Leifer, Becky S, Schiavoni, Richard P, Jiang, Nan, Choudhary, Amit, Westcott, Peter MK, Koehler, Angela N (March 2025) Small molecule modulators of TOX protein re-invigorate T cell activity. bioRxiv. ISSN 2692-8205 (Submitted)

PDF 10.1101.2025.03.03.641115.pdf - Submitted Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (10MB)

Abstract

The TOX protein (thymocyte selection-associated high mobility group box) is a critical transcription factor implicated in both T acute lymphoblastic leukemia (T-ALL) and CD8 + T cell exhaustion. Gene perturbation studies suggest that inhibiting TOX may have therapeutic implications for both leukemia and T cell exhaustion. However, due to its complex molecular mechanisms and intrinsically disordered structure, TOX has not been effectively targeted by small molecules to date. In this study, we used small molecule microarray (SMM) screening and biochemical assays to identify a series of TOX protein-protein interaction (PPI) inhibitors. We identified KI-TOX-A3 as a TOX protein binder and potent TOX PPI inhibitor. In T-ALL, KI-TOX-A3 revealed selective cytotoxicity and proteosome-dependent TOX degradation. In CD8 + T cells, KI-TOX-A3 potently reversed T cell exhaustion by decreasing surface inhibitory receptors, increasing expression of effector cytokines, and enhancing cancer cell killing activity. We also demonstrate the utility of KI-TOX-A3 to probe potential epigenetic regulatory mechanisms of TOX via KAT7 acetylation in T cells.

Item Type:	Paper
Subjects:	organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions
CSHL Authors:	Westcott, Peter
Communities:	CSHL labs > Westcott lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	10 March 2025
Date Deposited:	15 Sep 2025 12:46
Last Modified:	15 Sep 2025 12:46
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41964

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