This study used in silico compound screening to discover novel inhibitors of pancreatic cancer. Researchers screened a drug-like compound library to find molecules with high binding affinity for GSK-3, a protein kinase linked to pancreatic cancer cell apoptosis. Three compounds were identified that strongly bind to GSK-3 isoenzymes, have low toxicity, and could theoretically be administered orally. Future work will involve in vitro testing of these compounds and modifying their structures to analyze effects on binding affinity.

1. Novel Lead Compounds to Treat Pancreatic Cancer
Discovered Using In Silico Compound Screening
Joshua D. Gallo and Dr. Peter C. Anderson
University of Washington Bothell, School of STEM, Physical Sciences Division
❖Peter Anderson Research Lab
❖School of STEM, University of Washington Bothell
Introduction
Objective
Methodology Results Conclusion
Acknowledgements
• Approximately 459,000 people were diagnosed
with pancreatic cancer on a global scale in 2018,
where the five-year survival rate was about 6%.1
• While remedies like chemotherapy, surgery, and
radiotherapy are used regularly to ease the
burden of pancreatic cancer, there currently is no
specific treatment.2
• Glycogen Synthase Kinase 3 (GSK-3) is a
protein kinase that, when inhibited, is capable of
inducing apoptosis in pancreatic cancer cells
(Figure 1).3
• To discover potential inhibitors of pancreatic
cancer with very high binding affinity for GSK-3
and low toxicity levels using molecular modelling.
1. Bioactivity data for both the known active and
inactive compounds of the GSK-3A and GSK-3B
enzymes (isoenzymes of GSK-3) was extracted
from the ChEMBL database using R software.
2. Utilizing random forest machine learning, a
regression model was created to predict logarithmic
values of IC50 and Ki.
3. Once the regression model was calibrated to the
predicted log IC50 and log Ki values, a drug-like
compound library was screened to find compounds
with very high binding affinity and low Ki values
(Figure 2).
4. After these drug-like compounds were obtained,
specific compounds were selected that can strongly
bind to the active sites of both the GSK-3A and
GSK-3B enzymes.
5. Finally, toxicity levels were predicted for the
selected compounds via ADMET prediction on
admetSAR.
• Eight compounds that are able to inhibit the
GSK-3 isoenzymes were found (Table 1).
• Of those eight, three compounds are non-toxic
non-inhibitors that can theoretically pass through
the intestinal wall into the blood and would not
inhibit the hERG gene (Figures 3, 4, 5).
• Three drug-like compounds that have very high
binding affinity (Ki < 100 nM) towards GSK-3A
and GSK-3B were discovered.
• These compounds can bind to multiple drug
targets, exploiting polypharmacology.
Figure 1. GSK-3B Protein Structure
Active Site
Figure 2. GSK-3B Compound Screening
1. McGuigan, A., Kelly, P., Turkington, R. C., Jones, C.,
Coleman, H. G., & McCain, R. S. (2018, November 21).
Pancreatic cancer: A review of clinical diagnosis,
epidemiology, treatment and outcomes. Retrieved June 6,
2019, from
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250924/
2. Rawla, P., Sunkara, T., & Gaduputi, V. (2019, February).
Epidemiology of Pancreatic Cancer: Global Trends, Etiology
and Risk Factors. Retrieved June 6, 2019, from
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396775/
3. Marchand, Beno, Tremblay, Isabelle, Boucher, & Marie-
Josée. (2011, December 26). Inhibition of glycogen synthase
kinase-3 activity triggers an apoptotic response in pancreatic
cancer cells through JNK-dependent mechanisms. Retrieved
June 6, 2019, from
https://academic.oup.com/carcin/article/33/3/529/2463986
• In vitro testing on the three drug-like compounds,
adding different functional groups to them to see
how their binding affinities are affected..
References
Future Work
Table 1. Drug-like Compound Screening Results
Figure 4. Compound 2: 6-[2-[(2~{S},6~{R})-6-[2-(6-
quinolyl)ethyl]-2-piperidyl]ethyl]quinoline
Figure 3. Compound 1: 4-[2-[(2~{S},6~{R})-6-[2-
(4-quinolyl)ethyl]-2-piperidyl]ethyl]quinoline
Figure 5. Compound 4: (2~{S})-3-[(2~{R},6~{S})-2,6-bis[2-
(1,3-benzodioxol-5-yl)ethyl]-1-piperidyl]propane-1,2-diol