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

25 October 2019, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Deubiquitinating enzymes are a growing target class across multiple disease states, with several inhibitors now reported. b-AP15 and VLX1570 are two structurally related USP14/UCH-37 inhibitors with a shared α,β-unsaturated carbonyl substructure motif. Initially taken forward into a phase I/II clinical trial for refractory multiple myeloma, VLX1570 has since been put on full clinical hold due to dose limiting toxicity. Through a proteomic approach, here 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 through cross-linking, providing a molecular explanation for general cellular toxicity.

Keywords

chemical proteomics
ubiquitin
CIAPIN1
b-AP15
VLX1570

Supplementary materials

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VLX Manuscript Submission
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VLX Supporting information Submission
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Supporting Dataset 1
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Supplementary weblinks

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