| InChI | InChI=1S/C26H36N6O2/c33-25(21-5-2-6-21)28-11-3-10-27-24-23(20-8-9-20)17-29-26(31-24)30-22-7-1-4-19(16-22)18-32-12-14-34-15-13-32/h1,4,7,16-17,20-21H,2-3,5-6,8-15,18H2,(H,28,33)(H2,27,29,30,31) |
| Reference | 1. J Biol Chem. 2015 May 1;290(18):11376-83. doi: 10.1074/jbc.C114.627778. Epub 2015 Apr 1.<br />
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Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy.<br />
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Petherick KJ(1), Conway OJ(1), Mpamhanga C(2), Osborne SA(2), Kamal A(2), Saxty B(2), Ganley IG(3).<br />
Author information:<br />
(1)From the Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland and. (2)the MRC Technology Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, United Kingdom. (3)From the Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland and [email protected].<br />
Erratum in<br />
J Biol Chem. 2015 Nov 27;290(48):28726.<br />
Autophagy is a cell-protective and degradative process that recycles damaged and long-lived cellular components. Cancer cells are thought to take advantage of autophagy to help them to cope with the stress of tumorigenesis; thus targeting autophagy is an attractive therapeutic approach. However, there are currently no specific inhibitors of autophagy. ULK1, a serine/threonine protein kinase, is essential for the initial stages of autophagy, and here we report that two compounds, MRT67307 and MRT68921, potently inhibit ULK1 and ULK2 in vitro and block autophagy in cells. Using a drug-resistant ULK1 mutant, we show that the autophagy-inhibiting capacity of the compounds is specifically through ULK1. ULK1 inhibition results in accumulation of stalled early autophagosomal structures, indicating a role for ULK1 in the maturation of autophagosomes as well as initiation.<br />
2. Biochem J. 2011 Feb 15;434(1):93-104. doi: 10.1042/BJ20101701.<br />
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Novel cross-talk within the IKK family controls innate immunity.<br />
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Clark K(1), Peggie M, Plater L, Sorcek RJ, Young ER, Madwed JB, Hough J, McIver EG, Cohen P.<br />
Author information:<br />
(1)MRC Protein Phosphorylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, Scotland, U.K.<br />
Comment in<br />
Biochem J. 2011 Feb 15;434(1):e1-2.<br />
Members of the IKK {IκB [inhibitor of NF-κB (nuclear factor κB)] kinase} family play a central role in innate immunity by inducing NF-κB- and IRF [IFN (interferon) regulatory factor]-dependent gene transcription programmes required for the production of pro-inflammatory cytokines and IFNs. However, the molecular mechanisms that activate these protein kinases and their complement of physiological substrates remain poorly defined. Using MRT67307, a novel inhibitor of IKKϵ/TBK1 (TANK {TRAF [TNF (tumour-necrosis-factor)-receptor-associated factor]-associated NF-κB activator}-binding kinase 1) and BI605906, a novel inhibitor of IKKβ, we demonstrate that two different signalling pathways participate in the activation of the IKK-related protein kinases by ligands that activate the IL-1 (interleukin-1), TLR (Toll-like receptor) 3 and TLR4 receptors. One signalling pathway is mediated by the canonical IKKs, which directly phosphorylate and activate IKKϵ and TBK1, whereas the second pathway appears to culminate in the autocatalytic activation of the IKK-related kinases. In contrast, the TNFα-induced activation of the IKK-related kinases is mediated solely by the canonical IKKs. In turn, the IKK-related kinases phosphorylate the catalytic subunits of the canonical IKKs and their regulatory subunit NEMO (NF-κB essential modulator), which is associated with reduced IKKα/β activity and NF-κB-dependent gene transcription. We also show that the canonical IKKs and the IKK-related kinases not only have unique physiological substrates, such as IκBα, p105, RelA (IKKα and IKKβ) and IRF3 (IKKϵ and TBK1), but also have several substrates in common, including the catalytic and regulatory (NEMO and TANK) subunits of the IKKs themselves. Taken together, our studies reveal that the canonical IKKs and the IKK-related kinases regulate each other by an intricate network involving phosphorylation of their catalytic and regulatory (NEMO and TANK) subunits to balance their activities during innate immunity.
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