title: Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics.
abstract: Constitutively activated STAT3 protein has been found to be a key regulator of pancreatic cancer and a target for molecular therapeutic intervention. In this study, PG-S3-001, a small molecule derived from the SH-4-54 class of STAT3 inhibitors, was found to inhibit patient-derived pancreatic cancer cell proliferation in vitro and in vivo in the low micromolar range. PG-S3-001 binds the STAT3 protein potently, Kd = 324 nmol/L by surface plasmon resonance, and showed no effect in a kinome screen (>100 cancer-relevant kinases). In vitro studies demonstrated potent cell killing as well as inhibition of STAT3 activation in pancreatic cancer cells. To better model the tumor and its microenvironment, we utilized three-dimensional (3D) cultures of patient-derived pancreatic cancer cells in the absence and presence of cancer-associated fibroblasts (CAF). In this coculture model, inhibition of tumor growth is maintained following STAT3 inhibition in the presence of CAFs. Confocal microscopy was used to verify tumor cell death following treatment of 3D cocultures with PG-S3-001. The 3D model was predictive of in vivo efficacy as significant tumor growth inhibition was observed upon administration of PG-S3-001. These studies showed that the inhibition of STAT3 was able to impact the survival of tumor cells in a relevant 3D model, as well as in a xenograft model using patient-derived cells. Mol Cancer Ther; 15(5); 794-805. ©2016 AACR.
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Carolyn C
authors.initials: CC
authors.lastname: Arpin
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Mac
authors.affiliation: Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Huiwen
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Michelle
authors.initials: M
authors.lastname: Grimard
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Brent D G
authors.initials: BD
authors.lastname: Page
authors.affiliation: Department of Medicine, Division of Nephrology, Indiana Center for Biological Microscopy, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Malgorzata M
authors.initials: MM
authors.lastname: Kamocka
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Sina
authors.initials: S
authors.lastname: Haftchenary
authors.affiliation: Department of Physical and Environmental Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada.
authors.forename: Han
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Ball
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Rosa
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Ping-Shan
authors.initials: PS
authors.lastname: Lai
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Rodolfo F
authors.initials: RF
authors.lastname: Gómez-Biagi
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada. Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Ali
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Rahul
authors.initials: R
authors.lastname: Rana
authors.affiliation: Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana. Department of Pediatrics III, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany. Department of Otorhinolaryngology and Head/Neck Surgery (ENT), Heinrich Heine University, Dusseldorf, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.affiliation: Department of Physical and Environmental Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada.
authors.forename: Kagan
authors.initials: K
authors.lastname: Kerman
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Kyle C
authors.initials: KC
authors.lastname: McElyea
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: George E
authors.initials: GE
authors.lastname: Sandusky
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada. mfishel@iu.edu patrick.gunning@utoronto.ca.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
authors.affiliation: Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana. Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana. mfishel@iu.edu patrick.gunning@utoronto.ca.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Fishel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D018909:src Homology Domains
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D050796:STAT3 Transcription Factor