Author: Cai, Xiaoying ; Su, Kaiyue ; Jiang, Xueqin ; Zheng, Hongyu ; Yang, Jianhong ; Zhang, Xinlu ; Ye, Neng ; Peng, Jing ; Wu, Wenshuang ; Zhao, Min ; Zhu, Jiangli ; Tang, Minghai ; Ye, Haoyu ; Zhang, Ruijia ; Li, Na

Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate–induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.

01 Sep 2015·Chemistry & Biology

Identification and Characterization of an Irreversible Inhibitor of CDK2

Article

Author: Anscombe, Elizabeth ; Newell, David R ; Stanley, Will A ; Noble, Martin E M ; Staunton, David ; Cano, Celine ; Danielson, U Helena ; Golding, Bernard T ; Meschini, Elisa ; Martin, Mathew P ; Wang, Lan Z ; Geitmann, Matthis ; Griffin, Roger J ; Endicott, Jane A ; Wedge, Stephen R ; Reuillon, Tristan ; Mora-Vidal, Regina

Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)-9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 2	New Zealand	University of Oxford	17 Sep 2015
Inflammation	Preclinical	China	West China Hospital	09 Feb 2024

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