title: First-in-class small molecule potentiators of cancer virotherapy.
abstract: The use of engineered viral strains such as gene therapy vectors and oncolytic viruses (OV) to selectively destroy cancer cells is poised to make a major impact in the clinic and revolutionize cancer therapy. In particular, several studies have shown that OV therapy is safe and well tolerated in humans and can infect a broad range of cancers. Yet in clinical studies OV therapy has highly variable response rates. The heterogeneous nature of tumors is widely accepted to be a major obstacle for OV therapeutics and highlights a need for strategies to improve viral replication efficacy. Here, we describe the development of a new class of small molecules for selectively enhancing OV replication in cancer tissue. Medicinal chemistry studies led to the identification of compounds that enhance multiple OVs and gene therapy vectors. Lead compounds increase OV growth up to 2000-fold in vitro and demonstrate remarkable selectivity for cancer cells over normal tissue ex vivo and in vivo. These small molecules also demonstrate enhanced stability with reduced electrophilicity and are highly tolerated in animals. This pharmacoviral approach expands the scope of OVs to include resistant tumors, further potentiating this transformative therapy. It is easily foreseeable that this approach can be applied to therapeutically enhance other attenuated viral vectors.
authors.affiliation: Departments of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Dornan
authors.affiliation: Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Ramya
authors.initials: R
authors.lastname: Krishnan
authors.affiliation: Department of Chemistry and Institute of Biochemistry, Carleton University, Ottawa, Ontario, Canada.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Macklin
authors.affiliation: Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Selman
authors.affiliation: Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Nader
authors.initials: N
authors.lastname: El Sayes
authors.affiliation: Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Hwan Hee
authors.initials: HH
authors.lastname: Son
authors.affiliation: Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Colin
authors.initials: C
authors.lastname: Davis
authors.affiliation: Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chen
authors.affiliation: Departments of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Kerkeslin
authors.initials: K
authors.lastname: Keillor
authors.affiliation: Departments of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Penny J
authors.initials: PJ
authors.lastname: Le
authors.affiliation: Departments of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Moi
authors.affiliation: Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Paula
authors.initials: P
authors.lastname: Ou
authors.affiliation: Departments of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pardin
authors.affiliation: Department of Chemistry and Institute of Biochemistry, Carleton University, Ottawa, Ontario, Canada.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Canez
authors.affiliation: Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Le Boeuf
authors.affiliation: Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.affiliation: Department of Chemistry and Institute of Biochemistry, Carleton University, Ottawa, Ontario, Canada.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Smith
authors.affiliation: Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Jean-Simon
authors.initials: JS
authors.lastname: Diallo
authors.affiliation: Departments of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Boddy
mesh_terms: D000230:Adenocarcinoma / Q000628:therapy; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000628:therapy; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005260:Female; D005663:Furans / Q000494:pharmacology*; D005978:Glutathione / Q000032:analysis; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D044967:Serum; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014763:Viral Matrix Proteins / Q000172:deficiency / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D005663:Furans; D017874:Immediate-Early Proteins; C094460:M protein, Vesicular stomatitis virus; D014763:Viral Matrix Proteins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; D005978:Glutathione