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Chemoproteomic Profiling of Covalent XPO1 Inhibitors to Assess Target Engagement and Selectivity
- Source :
- ChemBioChem. 22:2116-2123
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- Selinexor, a covalent XPO1 inhibitor, is approved in the USA in combination with dexamethasone for penta-refractory multiple myeloma. Additional XPO1 covalent inhibitors are currently in clinical trials for multiple diseases including hematologic malignancies, solid tumor malignancies, glioblastoma multiforme (GBM), and amyotrophic lateral sclerosis (ALS). It is important to measure the target engagement and selectivity of covalent inhibitors to understand the degree of engagement needed for efficacy, while avoiding both mechanism-based and off-target toxicity. Herein, we report clickable probes based on the XPO1 inhibitors selinexor and eltanexor for the labeling of XPO1 in live cells to assess target engagement and selectivity. We used mass spectrometry-based chemoproteomic workflows to profile the proteome-wide selectivity of selinexor and eltanexor and show that they are highly selective for XPO1. Thermal profiling analysis of selinexor further offers an orthogonal approach to measure XPO1 engagement in live cells. We believe these probes and assays will serve as useful tools to further interrogate the biology of XPO1 and its inhibition in cellular and in vivo systems.
- Subjects :
- Receptors, Cytoplasmic and Nuclear
Antineoplastic Agents
Karyopherins
010402 general chemistry
01 natural sciences
Biochemistry
XPO1
In vivo
Cell Line, Tumor
medicine
Humans
Solid tumor
Molecular Biology
010405 organic chemistry
Mechanism (biology)
Amyotrophic Lateral Sclerosis
Organic Chemistry
Target engagement
Triazoles
medicine.disease
0104 chemical sciences
Hydrazines
Covalent bond
Cancer research
Molecular Medicine
Glioblastoma
Selectivity
Subjects
Details
- ISSN :
- 14397633 and 14394227
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- ChemBioChem
- Accession number :
- edsair.doi.dedup.....cc009095184e140535a099fc523099fa