title: COTI-2, a novel small molecule that is active against multiple human cancer cell lines in vitro and in vivo.
abstract: Identification of novel anti-cancer compounds with high efficacy and low toxicity is critical in drug development. High-throughput screening and other such strategies are generally resource-intensive. Therefore, in silico computer-aided drug design has gained rapid acceptance and popularity. We employed our proprietary computational platform (CHEMSAS®), which uses a unique combination of traditional and modern pharmacology principles, statistical modeling, medicinal chemistry, and machine-learning technologies to discover and optimize novel compounds that could target various cancers. COTI-2 is a small molecule candidate anti-cancer drug identified using CHEMSAS. This study describes the in vitro and in vivo evaluation of COTI-2. Our data demonstrate that COTI-2 is effective against a diverse group of human cancer cell lines regardless of their tissue of origin or genetic makeup. Most treated cancer cell lines were sensitive to COTI-2 at nanomolar concentrations. When compared to traditional chemotherapy or targeted-therapy agents, COTI-2 showed superior activity against tumor cells, in vitro and in vivo. Despite its potent anti-tumor efficacy, COTI-2 was safe and well-tolerated in vivo. Although the mechanism of action of COTI-2 is still under investigation, preliminary results indicate that it is not a traditional kinase or an Hsp90 inhibitor.
authors.affiliation: Critical Outcome Technologies Inc., London, Ontario, Canada.
authors.forename: Kowthar Y
authors.initials: KY
authors.lastname: Salim
authors.affiliation: Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Saman
authors.initials: S
authors.lastname: Maleki Vareki
authors.affiliation: Critical Outcome Technologies Inc., London, Ontario, Canada.
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Danter
authors.affiliation: Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada.|Department of Microbiology and Immunology, Western University, London, Ontario, Canada.|Department of Pathology, Western University, London, Ontario, Canada.|Department of Oncology, Western University, London, Ontario, Canada.|Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Koropatnick
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000634:Aminoquinolines / Q000302:isolation & purification / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D055808:Drug Discovery; D005260:Female; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013882:Thiosemicarbazones / Q000302:isolation & purification / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; C000625865:COTI-2 compound; D018841:HSP90 Heat-Shock Proteins; D013882:Thiosemicarbazones; D000251:Adenosine Triphosphatases
keywords: CHEMSAS; COTI-2; cancer; small molecule; targeted-therapy