Enhancing the C-48 STAT3 InhibitorDarnell FordDr. Nagarajan VaidehiDepartment of ImmunologyCity of Hope, Duarte, CaSoCalBSI 2008
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
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
Overview STAT3
pathway and structure C-48, the inhibitor/lead compound
Maestro Glide Prime
Scoring Rankings Future Steps
Signal Transduction Pathway
Activates Transcription
www.biocarta.com/pathfiles/m_stat3Pathway.asp
Dimerized and Localized to the nucleus
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
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
C-48
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
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
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
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
Maestro
Maestro
Glide Prime
Ligand DockingBinding Mode
Predictions
Protein Structure Prediction
Ligand Induced Fit
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
Future Steps
Testing 1: Dish Culture
Testing 2: Lab Animals
Clinical Trials
FDA Approval
Chemist
Manufacturer
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