A probe for NLRP3 inflammasome inhibitor MCC950 identifies carbonic anhydrase 2 as a novel target
File(s)
Published version
Supporting information
Author(s)
Type
Journal Article
Abstract
Inhibition of inflammasome and pyroptotic pathways are promising strategies for clinical treatment of autoimmune and inflammatory disorders. MCC950, a potent inhibitor of the NLR-family inflammasome pyrin domain-containing 3 (NLRP3) protein, has shown encouraging results in animal models for a range of conditions; however, until now, no off-targets have been identified. Herein, we report the design, synthesis, and application of a novel photoaffinity alkyne-tagged probe for MCC950 (IMP2070) which shows direct engagement with NLRP3 and inhibition of inflammasome activation in macrophages. Affinity-based chemical proteomics in live macrophages identified several potential off-targets, including carbonic anhydrase 2 (CA2) as a specific target of IMP2070, and independent cellular thermal proteomic profiling revealed stabilization of CA2 by MCC950. MCC950 displayed noncompetitive inhibition of CA2 activity, confirming carbonic anhydrase as an off-target class for this compound. These data highlight potential biological mechanisms through which MCC950 and derivatives may exhibit off-target effects in preclinical or clinical studies.
Date Issued
2021-06-18
Date Acceptance
2021-05-10
Citation
ACS Chemical Biology, 2021, 16 (6), pp.982-990
ISSN
1554-8929
Publisher
American Chemical Society
Start Page
982
End Page
990
Journal / Book Title
ACS Chemical Biology
Volume
16
Issue
6
Copyright Statement
© 2021 The Authors. Published byAmerican Chemical Society. This article is available open access under a CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/)
Sponsor
Wellcome Trust
Medical Research Council (MRC)
Grant Number
108246/Z/15/Z
MR/P022138/1
Subjects
Organic Chemistry
03 Chemical Sciences
06 Biological Sciences
Publication Status
Published
Date Publish Online
2021-05-18