1. Enhancing the C-48 STAT3 Inhibitor
Darnell Ford
Dr. Nagarajan Vaidehi
Department of Immunology
City of Hope, Duarte, Ca
SoCalBSI 2008

2. 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
Funding
Pilot funding
American society of Oncology
Cell proliferation, inhibits Apoptosis, Induce immunosuppression

3. 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

4. Overview STAT3 Maestro Scoring Rankings Future Steps
pathway and structure
C-48, the inhibitor/lead compound
Maestro
Glide
Prime
Scoring
Rankings
Future Steps

5. Signal Transduction Pathway
Dimerized and Localized to the nucleus
Activates Transcription

6. Crystal Structure of STAT3 Dimer
Src Homology 2 Domain
(SH2)
Connector Domain
Coiled Domain
DNA Binding Domain

7. 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

8. C-48

9. C-48 (cont.) Environment Distance between Heavy Atoms Changes
Arginine, Serine, Glutamine
Polar and hydrophilic
Distance between Heavy Atoms
Average of 3.0Å
Changes
Added CH2OH
GLU 555
SER 556
ARG 553
GLU 557

10. C-48 (cont.) Environment Distance between heavy atoms Changes
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
ILE 518
MET 1100

11. C-48 (cont.) Environment Distance Between Heavy Atoms Changes
Asparagine, Serine, Glutamine, Arginine
Highly Polar, Hydrophilic
Distance Between Heavy Atoms
Average of 3.5 Å
Changes
Additional Nitrogen Atom
NH2 and OH
SER 556
GLU 517
ARG 553
ASN 1099

12. 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
Develops High Performance Computational Technology since 1990
Products ranging from general molecular modeling programs to drug design software including both ligand and structure based methods.

13. Maestro

14. Bind Energy Kcal/mol
Glidescore
C-48.1
C-48
C-48.2
C-48.3
C-48.4
C-48.5
C-48.6
C-48.7
C-48.8
C-48.9
C-48.10
C-48.11
C-48.12
C-48.13
C-48.14
C-48.15
C-48.16
C-48.17
C-48.18
C-48.19

15. Future Steps Manufacturer FDA Approval Clinical Trials
Testing 2: Lab Animals
Testing 1: Dish Culture
Chemist

16. 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