1 Chapter 05 Enzyme Inhibition and Inactivation. 2 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 5.1 Schematic depiction of epidermal growth.

1 Chapter 05 Enzyme Inhibition and Inactivation

2 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 5.1 Schematic depiction of epidermal growth factor (EGF) and its receptor, activation of which leads to cell growth and proliferation. In its activated state, the EGFR normally functions in a dimeric form, as shown. Adapted from Pawson, T.; Jorgensen, C. Signal Transduction by Growth Factor Receptors (Chapter 11) In The Molecular Basis of Cancer, 3rd ed. Mendelsohn, J.; Howley, P.M.; Israel, M. A.; Gray, J. W.; Thompson, C. B. (Eds.), Elsevier, 2008, pp. 155–168.

3 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 5.2 (A) Schematic drawing of the interactions of erlotinib (5.13) with the active site of EGFR kinase. Modified image from PoseView (University of Hamburg, Germany) created from Protein Data Bank ID 1M17. EGFR residue numbering corresponds to that in PDB 2ITX. (B) Three- dimensional structure of erlotinib (green) bound to EGFR kinase (selected residues shown in blue). Data from Protein Data Bank ID 1M17 modified using Accelrys DS Viewer software. (PDB ID:1M17). Stamos, J., Sliwkowski, M.X., Eigenbrot, C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J. Biol. Chem. 2002, 277, 46265–46272.

4 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 5.3 Schematic drawing of the interactions of stable ATP analog AMP-PNP (5.14) with the active site of EGFR kinase. Modified image from PoseView (University of Hamburg, Germany) created from Protein Data Bank ID 2ITX. PDB ID: 2ITX (Yun, C.-H., Boggon, T.J., Li, Y., Woo, S., Greulich, H., Meyerson, M., Eck, M.J. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 2007, 11, 217–227.)

5 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 5.4 Ribbon representations of the structure of the Abl kinase domain (green) in complex with (A) PD173955 and (B) imatinib (originally known as STI-571). The protein strand colored red in (A) and blue in (B) is the “activation loop” of the kinase; the arrow points to the N-methylpiperazine portion of imatinib. Adapted by permission from the American Association for Cancer Research: Nagar, B. et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res. 2002, 62, 4236–4243.

10 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 5.9 Hypothetical active site of carboxypeptidase A. Adapted with permission from Cushman, D. W., Cheung, H. S., Sabo, E. F., Ondetti, M. A. Biochemistry 1977 16, 5484. Copyright © 1977 American Chemical Society

12 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 5.11 Hypothetical binding of carboxyalkanoylproline and mercaptoalkanoylproline derivatives to ACE. Adapted with permission from Cushman, D. W., Cheung, H. S., Sabo, E. F., Ondetti, M. A. Biochemistry 1977 16, 5484. Copyright © 1977 American Chemical Society

13 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 5.12 Lead design for C 2 symmetric inhibitors of HIV protease based on the structure of the tetrahedral intermediate during hydrolysis of HIV protease

16 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 5.2 Equilibrium between active and inactive conformations of Abl kinase, where the active conformation binds to ATP, leading to catalysis of the normal enzymatic reaction; the inhibitor imatinib binds to and stabilizes the inactive form, pulling the equilibrium to the right.

1 Chapter 05 Enzyme Inhibition and Inactivation. 2 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 5.1 Schematic depiction of epidermal growth.

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1 Chapter 05 Enzyme Inhibition and Inactivation. 2 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 5.1 Schematic depiction of epidermal growth.

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Presentation on theme: "1 Chapter 05 Enzyme Inhibition and Inactivation. 2 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 5.1 Schematic depiction of epidermal growth."— Presentation transcript:

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