Development of Small Molecule Inhibitors of the Lethal Factor in Anthrax. Brian Englund Michigan State University September 13, 2006
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1 Development of mall Molecule Inhibitors of the Lethal Factor in Anthrax Brian Englund Michigan tate University eptember 13, 2006
2 Introduction Proteolysis Mechanism Anthrax Inhibitors Panchal and Bavari Pellechia Quinn Merck Conclusions Acknowledgements utline
3 Introduction Proteolysis Mechanism Anthrax Inhibitors Panchal and Bavari Pellechia Quinn Merck Conclusions Acknowledgements utline
4 Current Treatment Vaccination nly for people at high risk Joint symptoms and gastrointestinal problems Antibiotics Ciprofloxacin F Doxycycline 2 Geier, D.A.; Geier, M.R. in Exp Rheumatol. 2002, 20, 217 Geier, D.A.; Geier, M..R. epatogastroenterology. 2004, 51, 762
5 Life Cycle of Anthrax Caused by Bacillus anthracis pores are absorbed by macrophages in the lungs pores are transported to lymph nodes Abrami, L.; Reig,.; van der Goot, F. Trends Microbiol. 2005, 13, 72
6 Dixon, T.C.. Engl. J. Med. 1999, 341, 815 Fukao T. Lancet Infectious Diseases 2004, 4, 166 ow Anthrax Kills
7 A-B exotoxin The Anthrax Toxin Tripartite Protective antigen (PA) Lethal factor (LF) Edema factor (EF) eaves mitogen activated protein kinase kinase (MAPKK) Park, J.M. et. al. cience. 2002, 297, 2048
8 Cell Membrane Anthrax Toxin Receptor PA 83 PA 63 PA 20 LF or EF von eijne, G. cience. 2005, 309, 709
9 MAPKK Pathway Taken from Fukao T. Lancet Infectious Diseases 2004, 4, 166
10 Introduction Proteolysis Mechanism Anthrax Inhibitors Panchal and Bavari Pellechia Quinn Merck Conclusions Acknowledgements utline
11 Lethal Factor Crystal tructure 2.1Å 2.7Å Zn +2 2 Zn +2 Liddington, R.C. et. al. ature. 2001, 414, 229
12 Lethal Factor and MAPKK Liddington, R.C. et. al. ature. 2001, 414, 229
13 Lethal factor and MAPKK (cont.) Liddington, R.C. et. al. ature. 2001, 414, 229
14 Thermolysin as a Model is Thermolysin Zn 2+ is Glu Lethal Factor is Zn 2+ is Glu Blomberg, M.R.A.; Pelmenschikov, V. J. Biol. Inorg. Chem. 2002, 7, 284
15 3 2 MAPKK Zn 2+ C is Zn 2+ is C Glu is is Glu is Zn 2+ is C Glu is Zn 2+ is C Glu is Zn 2+ is C Glu
16 Introduction Proteolysis Mechanism Anthrax Inhibitors Panchal and Bavari Pellechia Quinn Merck Conclusions Acknowledgements utline
17 Drug Discovery igh throughput screening (T) Large library igher molecular weight Fluorescence based screening Fragment-based drug design maller library Lower molecular weight impler molecules Weaker inhibition estler,.p. Curr. Drug Disc. Tech. 2005, 2, 1
18 Fluorescence Detection in T Anthrax Lethal Toxin o Fluorescence Fluorescence Me 2 C 2 2 Panchal, R.G. et. al. at. truct. Mol. Bio. 2004, 11, 67
19 Fluorescence Experiment EPE p nm lethal factor 20μM inhibitor Fluorescent peptide substrate Measure emission every minute for 30 minutes Panchal, R.G. et. al. at. truct. Mol. Bio. 2004, 11, 67
20 19 F MR Detection in Fragment Based Design Fragment A eavage ite Fragment B Pellechia, M. et. al. Proc. atl. Acad. ci. 2005, 102, 9499
21 Verifying Leads With PLC All screening studies verified their promising results with PLC Inhibitors can quench some fluorescence Quenching from inhibitor leads to inaccurate IC 50
22 Introduction Proteolysis Mechanism Anthrax Inhibitors Panchal and Bavari Pellechia Quinn Merck Conclusions Acknowledgements utline
23 Active Compounds tructure % inhibition at 20μM ID number 3 C 2 C PB PB-2 90 PB-3 90 PB-4 Panchal, R.G.; Bavari,. et. al. at. truct. Mol. Bio. 2004, 11, 67
24 LF Complexed With PB-1 3 C C Panchal, R.G.; Bavari,. et. al. at. truct. Mol. Bio. 2004, 11, 67
25 Developing a Pharmacophore Taken directly from at. truct. Mol. Bio. 2004, 11, 67 C 6.5 A F D B 3.1 E Panchal, R.G.; Bavari,. et. al. at. truct. Mol. Bio. 2004, 11, 67
26 Examining the Pharmacophore 3 C C PB-1 PB-2 PB-3 PB-4 E D C B F A
27 Panchal ummary ydrogen bond acceptor in center Aromatic rings on either side of a linker If the linker is a hydrogen bond donor, it coordinates to glutamate ydrogen bond acceptors/donors at the end of the aromatic rings
28 Introduction Proteolysis Mechanism Anthrax Inhibitors Panchal and Bavari Pellechia Quinn Merck Conclusions Acknowledgements utline
29 Pellechia s caffold Fragment-based design it with an IC 50 of 140 μm MP-1 Pellechia, M. et. al. Proc. atl. Acad. ci. 2005, 102, 9499
30 R 1 R 2 Pellechia s caffold ID R 1 R 2 IC 50 (μm) ID R 1 R 2 IC 50 (μm) MP-2 C MP-7 20 F 3 C 2 MP-3 C MP MP MP-5 C MP MP-10 I 5.5 MP MP Pellechia, M. et. al. Proc. atl. Acad. ci. 2005, 102, 9499
31 Varying the Acid ide Chain ID R 1 R 2 IC 50 (μm) MP-12 MP-13 Br Br MP R 1 R 2 MP Pellechia, M. et. al. Proc. atl. Acad. ci. 2005, 102, 9499
32 ID R 1 IC 50 (μm) Varying the R 1 Ring MP MP-14 MP-13 Br R 1 MP MP-18 3 C 0.30 MP-19 MP-20 F 3 C Pellechia, M. et. al. Proc. atl. Acad. ci. 2005, 102, 9499
33 ynthesis of MP-1 Derivatives () 2 B X Y + R I Pd(PPh 3 ) 4 1.2M a 2 C 3 PhMe Reflux R X Y R X Y R X DMF + Y MW C 2 C 2 Pellechia, M. et. al. J. Med. Chem. 2006, 49, 27
34 Varying the Furan Ring ID IC 50 (μm) MP MP MP Pellechia, M. et. al. J. Med. Chem. 2006, 49, 27
35 Varying the Thiazolidinone Ring ID IC 50 (μm) MP-20 F 3 C 0.19 MP-23 F 3 C 5.9 MP-24 F 3 C 3 C 100 Pellechia, M. et. al. J. Med. Chem. 2006, 49, 27
36 Applying the Pharmacophore PB-1 MP-11
37 LF Complexed With MP-11 C 2 Zn 2+ Pellechia, M. et. al. Proc. atl. Acad. ci. 2005, 102, 9499
38 Varying the Thiazolidinone Ring ID IC 50 (μm) MP-20 F 3 C 0.19 MP-23 F 3 C 5.9 MP-24 F 3 C 3 C 100 Pellechia, M. et. al. Proc. atl. Acad. ci. 2005, 102, 9499
39 Varying the Furan Ring ID IC 50 (μm) MP MP MP Pellechia, M. et. al. J. Med. Chem. 2006, 49, 27
40 Pellechia ummary ulfur strongly coordinates the zinc 2-phenyl furan serves as a core structure Carboxylic acid interacts with polar residues Confirms the importance of an aromatic ring
41 utline Introduction Proteolysis Mechanism Anthrax Inhibitors Panchal and Bavari Pellechia Quinn Merck Conclusions Acknowledgements
42 Quinn s Lead Compounds CF 3 Br MQ-1 MQ-2 MQ-3 IC 50 = 1.1 μm IC 50 = 1.8 μm IC 50 = 5.2 μm 2 3 C MQ-4 MQ-5 MQ-6 IC 50 = 4.8 μm IC 50 = 8.3 μm IC 50 = 10.0 μm Quinn, M. et. al. J. Med. Chem. 2006, 49, 5232
43 Quinn s Modeling tudy Modeled the compounds canned all conformations within 6 kcal/mol of global minimum Compared to Panchal and Bavari s pharmacophore Quinn, M. et. al. J. Med. Chem. 2006, 49, 5232
44 Quinn s Modeling tudy (cont.) Quinn, M. et. al. J. Med. Chem. 2006, 49, 5232
45 PB-1 Complexed with LF 3 C C Panchal, R.G.; Bavari,. et. al. at. truct. Mol. Bio. 2004, 11, 67
46 MQ-1 Manually Moved Into the Active ite
47 Introduction Proteolysis Mechanism Anthrax Inhibitors Panchal and Bavari Pellechia Quinn Merck Conclusions Acknowledgements utline
48 Merck Compounds Me Me Me YX-1 IC 50 = 1.2μM CF 3 Xiong, Y. et. al. Bioorg. Med. Chem. Lett. 2006, 16, 964
49 ynthesis of Derivatives + 1. DIEA DCM:DMF TF AA-FMC DIC DMF 2. DMF R 1 2 R 2 DIEA DMAP DCM-TF R 1 R 2 5% TFA DCM R 1 R 2 Xiong, Y. et. al. Bioorg. Med. Chem. Lett. 2006, 16, 964
50 tructure Activity Relationship tudy R 2 ID R IC 50 (μm) ID R IC 50 (μm) YX YX F YX YX YX YX F Me F YX YX Xiong, Y. et. al. Bioorg. Med. Chem. Lett. 2006, 16, 964 Me Me F Me F
51 MAPK Kinase in the Active ite Liddington, R.C. et. al. ature. 2001, 414, 229
52 AR tudy (cont.) Fluorescence R F Me Cell Culture ID R IC 50 (μm) ID R IC 50 (μm) YX-10 C YX-10 C YX YX YX YX YX YX Xiong, Y. et. al. Bioorg. Med. Chem. Lett. 2006, 16, 964
53 pecificity Protein Inhibition (μm) LF MMP MMP MMP MMP MMP Xiong, Y. et. al. Bioorg. Med. Chem. Lett. 2006, 16, 964
54 utline Introduction Proteolysis Mechanism Anthrax Inhibitors Panchal and Bavari Pellechia Quinn Conclusions Acknowledgements
55 Conclusions olving the crystal structure has led to several promising drugs for the inhibition of anthrax Effective drugs include ulfur moiety Free carboxyl group ydrogen bond acceptor Rigid aromatic rings
56 Acknowledgements Dr. Tepe Dr. Walker Monica Aman Teri, Tim, Jason, Adam, Chris, am, Amanda, Brandon, Thu
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