The substrate-activity-screening methodology applied to receptor tyrosine kinases: A proof-of-concept study

European Journal of Medicinal Chemistry

Volumn 57, Issue , 2012, Pages 1-9

  Chapelat, Julien ^a   Berst, Frédéric ^a   Marzinzik, Andreas L ^a   Moebitz, Henrik ^a   Drueckes, Peter ^a   Trappe, Joerg ^a   Fabbro, Doriano ^a   Seebach, Dieter ^b  

^a NOVARTIS PHARMA AG   (Switzerland)

^b ETH ZURICH   (Switzerland)

Author keywords

Insulin like Growth Factor 1 Receptor; Kinase inhibitor; Michaelis Menten kinetics; Protein protein interactions; Substrate Activity Screening

Indexed keywords

PHOSPHOTRANSFERASE INHIBITOR; PROTEIN TYROSINE KINASE; SOMATOMEDIN C RECEPTOR;

ARTICLE; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; ENZYME SUBSTRATE COMPLEX; MICHAELIS MENTEN KINETICS; PROTEIN PROTEIN INTERACTION; SCREENING;

ADENOSINE TRIPHOSPHATE; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; KINETICS; PEPTIDES; PROTEIN BINDING; PROTEIN KINASE INHIBITORS; RECEPTOR PROTEIN-TYROSINE KINASES; RECOMBINANT FUSION PROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY;

EID: 84867081732     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2012.08.038     Document Type: Article

References (18)

1. P. Cohen Nat. Rev. Drug Disc 1 2002 309 315
2. S.P. Davies, H. Reddy, M. Caivano, and P. Cohen Biochem. J. 351 2000 95 105
3. J. Bain, H. McLauchlan, M. Elliott, and P. Cohen Biochem. J. 371 2003 199 204
4. For a review on allosteric inhibitors see R.M. Eglen, and T. Reisine Expert Opin. Drug Discov. 5 2010 277 290
5. S.M. Sebti, Q. Cheng, A.D. Hamilton, K. Kayser-Bricker US2010/0009397 A1 (2010).
6. Litman Biochemistry 46 2007 4716 4724
7. Steiner Eur. J. Pharm. 562 2007 1 11
8. G. Ye, R. Tiwari, and K. Parang Curr. Opin. Investig. Drugs 9 2008 605 613
9. M.B. Soellner, K.A. Rawls, C. Grundner, T. Alber, and J.A. Ellman J. Am. Chem. Soc. 129 2007 9613 9615
10. J. Chapelat, F. Berst, A.L. Marzinzik, H. Moebitz, P. Drueckes, J. Trappe, and D. Seebach Bioorg. Med. Chem. Lett. 21 2011 7030 7033
11. N.W. Charter, L. Kauffman, R. Singh, and R.M. Eglen J. Biomol. Screen. 11 2006 390 399
12. The assay system is based on the detection of ADP formed during the course of the phosphorylation reaction and the lowest ADP concentration required for detection is 500 nM. This implied that the minimal substrate concentration still enabling accurate measurements while maintaining low substrate conversion (<20%) was situated around 2.5 μM.
13. The importance of the tryptophan residue and its interaction with the kinase was based on IGF-1R crystal structure PDB ID 1k3a.
14. For details see the Supplementary material.
15. M.H. Kim, J.H. Lai, and D.G. Hangauer Int. J. Pept. Protein Res. 44 1994 457 465
16. J. Alfaro-Lopez, W. Yuan, B.C. Phan, J. Kamath, Q. Lou, K.S. Lam, and V.J. Hruby J. Med. Chem. 41 1998 2252 2260
17. Z.-J. Yao, Y. Gao, and T.R. Burke Jr. Tetrahedron: Asymmetry 10 1999 3727 3734 (The detailed synthetic sequence is described in the Supplementary material)
18. D. Erdmann, C. Zimmermann, P. Fontana, J.-C. Hau, A. De Pover, and P. Chène J. Biomol. Technol. 21 2010 9 17