Re-evaluating the mechanism of action of α,β-unsaturated carbonyl DUB inhibitors b-AP15 and VLX1570: a paradigmatic example of unspecific protein crosslinking with Michael acceptor motif-containing drugs.

Ward, Jennifer A; Pinto-Fernandez, Adan; Cornelissen, Loïc; Bonham, Sarah; Díaz-Sáez, Laura; Riant, Olivier; Huber, Kilian V M; Kessler, Benedikt M; Feron, Olivier; Tate, Edward W

doi:10.1021/acs.jmedchem.0c00144

Re-evaluating the mechanism of action of α,β-unsaturated carbonyl DUB inhibitors b-AP15 and VLX1570: a paradigmatic example of unspecific protein crosslinking with Michael acceptor motif-containing drugs.

Ward, Jennifer A

;

Pinto-Fernandez, Adan

;

Cornelissen, Loïc

;

Bonham, Sarah

;

Tate, Edward W

;et.al.

(2020) Journal of Medicinal Chemistry — Vol. 63, n° 7, p. 3756-3762 (2020)

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Authors

Ward, Jennifer A
Author
Pinto-Fernandez, Adan
Author
Cornelissen, LoïcUCLouvain
Author
Bonham, Sarah
Author
Riant, OlivierUCLouvain
Author
Feron, OlivierUCLouvain
Author
Tate, Edward W
Author

Abstract

Deubiquitinating enzymes are a growing target class across multiple disease states, with several inhibitors now report-ed. b-AP15 and VLX1570 are two structurally related USP14/UCH-37 inhibitors. Through a proteomic approach, we demonstrate that these compounds target a diverse range of proteins, resulting in the formation of higher molecular weight complexes. Activity-based proteome profiling identified CIAPIN1 as a sub-micromolar covalent target of VLX1570, and further analysis demonstrated that high molecular weight complex formation leads to aggregation of CIAPIN1 in intact cells. Our results suggest that in addition to DUB inhibition, these compounds induce non-specific protein aggregation, providing a molecular explanation for general cellular toxicity.

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Ward, J. A., Pinto-Fernandez, A., Cornelissen, L., Bonham, S., Díaz-Sáez, L., Riant, O., Huber, K. V. M., Kessler, B. M., Feron, O., & Tate, E. W. (2020). Re-evaluating the mechanism of action of α,β-unsaturated carbonyl DUB inhibitors b-AP15 and VLX1570: a paradigmatic example of unspecific protein crosslinking with Michael acceptor motif-containing drugs. Journal of Medicinal Chemistry, 63(7), 3756-3762. https://doi.org/10.1021/acs.jmedchem.0c00144 (Original work published 2020)