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Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, Mathieson T, Perrin J, Raida M, Rau C, Reader V, Sweetman G, Bauer A, Bouwmeester T, Hopf C, Kruse U, Neubauer G, Ramsden N, Rick J, Kuster B, Drewes G. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol. 2007 Sep;25(9):1035-44. PubMed.
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Cellzome AG
Q&A with author. Questions by Gabrielle Strobel.
Q: What is the main thrust of the paper?
A: It showcases our chemoproteomics technology, which enables the fishing for a drug's targets directly in cells or crude tissue lysate. Because we use quantitative mass spectrometry, we measure, in one go, the drug's affinities for the targets.
Q: You have chosen Gleevec as a sample drug. Gleevec has received attention in the AD field because it appears to reduce Aβ levels. Netzer et al. (2003) reported it reduces Aβ generation in a cell-free system and N2a cells, and Fraering et al. (2005) proposed an ATP binding site on γ-secretase itself. Eisele et al. (2007) propose a different mechanism via neprilysin induction and increased Aβ degradation. One question is what exactly Gleevec binds to.
A: I think the Gleevec-Aβ story is very intriguing. The three studies you cited are not totally consistent with each other. It appears that the mechanism is still unclear. For instance, does the drug act via a direct binding site on the γ-secretase complex, or does it inhibit a kinase which phosphorylates APP, or one of the secretase components?
Q: Do your data address the issue?
A: We have looked for Gleevec targets in leukemia cells. We found the known ones and, despite 4,000 citations for this drug in PubMed, also two potent novel targets. Altogether there are now five targets: The Aβl, Kit, PDGFR and DDR kinases, and NQO2, an oxidoreductase and so far the only non-kinase target. One could speculate about which target is responsible for the Aβ effect. Of the ones we discovered, the receptor tyrosine kinase DDR1 appears to have some function in the brain as it is a susceptibility gene for schizophrenia. This could be interesting for the community to follow up. As a type I transmembrane protein, DDR1 might even be a γ-secretase substrate. It might also be interesting to profile targets of Gleevec in brain directly.
References:
Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, Bornmann WG, Clarkson B, Xu H, Greengard P. Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12444-9. PubMed.
Fraering PC, Ye W, LaVoie MJ, Ostaszewski BL, Selkoe DJ, Wolfe MS. gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site. J Biol Chem. 2005 Dec 23;280(51):41987-96. PubMed.
Eisele YS, Baumann M, Klebl B, Nordhammer C, Jucker M, Kilger E. Gleevec increases levels of the amyloid precursor protein intracellular domain and of the amyloid-beta degrading enzyme neprilysin. Mol Biol Cell. 2007 Sep;18(9):3591-600. PubMed.
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