High-volume cellular screening for anticancer agents with combinatorial chemical libraries: A new methodology

Sydney E. Salmon, Rosa H. Liu-Stevens, Yu Zhao, Michal Lebl, Viktor Krchñák, Ken Wertman, Nikolai Sepetov, Kit Lam

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


A single-step cancer cell cytotoxic assay system for anticancer drug discovery has been developed which facilitates rapid screening of large combinatorial chemical libraries synthesized using the 'one-bead-one-compound' (OBOC) methodology. Each OBOC library bead incorporates two orthogonally cleavable linkers that release the bead-bound compound at a different pH. The assay utilizes high concentrations of tumor cells mixed directly with OBOC beads and plated in soft agarose containing tissue culture medium. One of the orthogonal linkers is cleaved at neutral pH in tissue culture releasing an aliquot of compound to diffuse at a relatively high local concentration into the soft agarose immediately surrounding the bead. Active compounds are identified visually from a clear ring of tumor cell lysis which forms within 48 h around just the rare bead releasing a cytotoxic compound. The bead releasing a cytotoxin is then plucked from the agar and the remaining compound still linked to the bead can be released for structural analysis, followed by compound resynthesis and confirmatory testing. This assay system has been successfully applied to identification of lead cytotoxic compounds from model peptidic and nonpeptidic combinatorial chemical libraries. Use of this methodology may facilitate anticancer drug discovery.

Original languageEnglish (US)
Pages (from-to)57-63
Number of pages7
JournalMolecular Diversity
Issue number1-2
StatePublished - 1996
Externally publishedYes


  • Anticancer drugs
  • Combinatorial chemical libraries
  • Tumor cell line screening

ASJC Scopus subject areas

  • Chemistry (miscellaneous)
  • Drug Discovery
  • Organic Chemistry


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