title: Establishing a high-throughput and automated cancer cell proliferation panel for oncology lead optimization.
abstract: Tumor cell proliferation assays are widely used for oncology drug discovery, including target validation, lead compound identification, and optimization, as well as determination of compound off-target activities. Taking advantage of robotic systems to maintain cell culture and perform cell proliferation assays would greatly increase productivity and efficiency. Here we describe the establishment of automated systems for high-throughput cell proliferation assays in a panel of 13 human tumor cell lines. These cell lines were selected from various types of human tumors containing a broad range of well-characterized mutations in multiple cellular signaling pathways. Standard procedures for cell culture and assay performance were developed and optimized in each cell line. Moreover, in-house developed software (i.e., Toolset, Curvemaster, and Biobars) was applied to analyze the data and generate data reports. Using tool compounds, we have shown that results obtained through this panel exhibit high reproducibility over a long period. Furthermore, we have demonstrated that this panel can be used to identify sensitive and insensitive cell lines for specific cancer targets, to drive cellular structure-activity relationships, and to profile compound off-target activities. All those efforts are important for cancer drug discovery lead optimization.
authors.affiliation: 1Department of Lead Evaluation and Mechanistic Biochemistry, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Humberto
authors.initials: H
authors.lastname: Ribeiro
authors.forename: Garrett
authors.initials: G
authors.lastname: Kolodin
authors.forename: James
authors.initials: J
authors.lastname: Gill
authors.forename: Yu-Sun
authors.initials: YS
authors.lastname: Wang
authors.forename: Daniel
authors.initials: D
authors.lastname: Maloney
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.forename: Larnie
authors.initials: L
authors.lastname: Myer
authors.forename: Michael
authors.initials: M
authors.lastname: Beluch
authors.forename: Litao
authors.initials: L
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Schweizer
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D057205:Automation, Laboratory; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm; D057166:High-Throughput Screening Assays / Q000295:instrumentation / Q000592:standards*; D006801:Humans; D009928:Organ Specificity; D015203:Reproducibility of Results; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents
keywords: automation; cancer signaling pathways; lead optimization; panel screen; tumor cell proliferation assay