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A probe for NLRP3 inflammasome inhibitor MCC950 identifies carbonic anhydrase 2 as a novel target

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Title: A probe for NLRP3 inflammasome inhibitor MCC950 identifies carbonic anhydrase 2 as a novel target
Authors: Kennedy, C
Goya Grocin, A
Kovacic, T
Singh, R
Tate, E
Ward, J
Shenoy, A
Item 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.
Issue Date: 18-Jun-2021
Date of Acceptance: 10-May-2021
URI: http://hdl.handle.net/10044/1/89757
DOI: 10.1021/acschembio.1c00218
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/Funder: Wellcome Trust
Medical Research Council (MRC)
Funder's Grant Number: 108246/Z/15/Z
MR/P022138/1
Keywords: Organic Chemistry
03 Chemical Sciences
06 Biological Sciences
Publication Status: Published
Online Publication Date: 2021-05-18
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
Department of Infectious Diseases
Faculty of Natural Sciences



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