Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City...
-
date post
21-Dec-2015 -
Category
Documents
-
view
219 -
download
0
Transcript of Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City...
![Page 1: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/1.jpg)
Enhancing the C-48 STAT3 InhibitorDarnell FordDr. Nagarajan VaidehiDepartment of ImmunologyCity of Hope, Duarte, CaSoCalBSI 2008
![Page 2: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/2.jpg)
Background Signal Transducer and Activator of
Transcription 3 STAT3 mediates the expression of various genes
in response to cell stimuli STAT3 possesses oncogenic potential and anti-
apoptotic activities Constitutive activation of STAT3 found in over 20
human cancers Effective and STAT3 selective inhibitors have
not been found
![Page 3: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/3.jpg)
Objectives Create a Derivative of Lead Compound That
Possesses an Enhanced Binding Affinity and Selectivity to STAT3
Learn Maestro and Glide Construct ligands that contain rational additions to the
lead compound and create a file for those ligands Formulate a list of lead compound derivatives using
computer simulation and combinatorial screening whose binding energy scores are most favorable
![Page 4: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/4.jpg)
Overview STAT3
pathway and structure C-48, the inhibitor/lead compound
Maestro Glide Prime
Scoring Rankings Future Steps
![Page 5: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/5.jpg)
Signal Transduction Pathway
Activates Transcription
www.biocarta.com/pathfiles/m_stat3Pathway.asp
Dimerized and Localized to the nucleus
![Page 6: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/6.jpg)
Crystal Structure of STAT3 Dimer
Connector Domain
Src Homology 2 Domain(SH2)
Coiled Domain
DNA Binding Domain
www.brown.edu/news/2004-05/04-072.jpg
![Page 7: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/7.jpg)
STAT3 (Cont.) C-48
Tested experimentally at City of Hope Inhibits the dimer formation
Inhibits STAT3 DNA interaction Kills tumor cells
Promotes apoptosis in tumor cells
Goal: Derivatize C-48 to improve its binding affinity, efficacy, and selectivity with STAT3
![Page 8: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/8.jpg)
C-48
![Page 9: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/9.jpg)
C-48 (cont.) Environment
Arginine, Serine, Glutamine
Polar and hydrophilic
Distance between Heavy Atoms Average of 3.0Å
Changes Added CH2OH ARG
553
GLU 555
GLU 557
SER 556
![Page 10: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/10.jpg)
C-48 (cont.) Environment
Cysteine, Isoleucine, Methionine
Non-polar, Hydrophobic
Distance between heavy atoms Average of 4.8 Å
Changes Six carbon ring Hydroxyl group
CYS 1164
ILE 1105
MET 1100
ILE 518
![Page 11: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/11.jpg)
C-48 (cont.) Environment
Asparagine, Serine, Glutamine, Arginine
Highly Polar, Hydrophilic
Distance Between Heavy Atoms Average of 3.5 Å
Changes Additional
Nitrogen Atom NH2 and OH
ASN 1099
GLU 517
ARG 553
SER 556
![Page 12: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/12.jpg)
Maestro Product of Schrödinger
Designer of high performance computational technology Drug design software and general molecular modeling
Graphical User Interface (GUI) for all Schrodinger programs Tools to
build, display, and manipulate structures organize, monitor, submit, and visualize results from calculations
on structures
http://schrodinger.com
![Page 13: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/13.jpg)
Maestro
Maestro
Glide Prime
Ligand DockingBinding Mode
Predictions
Protein Structure Prediction
Ligand Induced Fit
![Page 14: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/14.jpg)
Bind Energy Kcal/mol Glidescore
C-48.1 -68.38266799 -5.013944
C-48 -66.21636123 -5.085172
C-48.2 -65.35318568 -4.634376
C-48.3 -64.4949882 -5.362646
C-48.4 -63.73290669 -7.198051
C-48.5 -62.89760652 -7.288412
C-48.6 -60.56520178 -4.944679
C-48.7 -60.01377425 -7.843053
C-48.8 -59.73756404 -7.708974
C-48.9 -59.25700937 -7.748304
C-48.10 -59.11006754 -6.536931
C-48.11 -58.85839462 -6.122557
C-48.12 -58.64722779 -4.387408
C-48.13 -57.31288197 -4.81971
C-48.14 -57.07387623 -6.655349
C-48.15 -56.07602975 -6.891117
C-48.16 -54.98854927 -4.520704
C-48.17 -54.4892643 -6.602773
C-48.18 -53.62711263 -3.81365
C-48.19 -53.02512129 -4.507152
![Page 15: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/15.jpg)
Future Steps
Testing 1: Dish Culture
Testing 2: Lab Animals
Clinical Trials
FDA Approval
Chemist
Manufacturer
![Page 16: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/16.jpg)
Acknowledgements Dr. Nagarajan Vaidehi Dr. JingPing Lin Dr. Supriyo Bhattacharya Dr. Spencer Hall Dr. Sandra Sharp Dr. Jamil Momand Dr. Wendie Johnston Dr. Nancy Warter-Perez SoCalBSI 2008
![Page 17: Enhancing the C-48 STAT3 Inhibitor Darnell Ford Dr. Nagarajan Vaidehi Department of Immunology City of Hope, Duarte, Ca SoCalBSI 2008.](https://reader030.fdocuments.in/reader030/viewer/2022032611/56649d575503460f94a3694f/html5/thumbnails/17.jpg)