In this section
@article{Kennedy:2021:10.1021/acschembio.1c00218,
author = {Kennedy, C and Goya, Grocin A and Kovacic, T and Singh, R and Tate, E and Ward, J and Shenoy, A},
doi = {10.1021/acschembio.1c00218},
journal = {ACS Chemical Biology},
pages = {982--990},
title = {A probe for NLRP3 inflammasome inhibitor MCC950 identifies carbonic anhydrase 2 as a novel target},
url = {http://dx.doi.org/10.1021/acschembio.1c00218},
volume = {16},
year = {2021}
}
TY - JOUR
AB - 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.
AU - Kennedy,C
AU - Goya,Grocin A
AU - Kovacic,T
AU - Singh,R
AU - Tate,E
AU - Ward,J
AU - Shenoy,A
DO - 10.1021/acschembio.1c00218
EP - 990
PY - 2021///
SN - 1554-8929
SP - 982
TI - A probe for NLRP3 inflammasome inhibitor MCC950 identifies carbonic anhydrase 2 as a novel target
T2 - ACS Chemical Biology
UR - http://dx.doi.org/10.1021/acschembio.1c00218
UR - http://hdl.handle.net/10044/1/89757
VL - 16
ER -
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