Identification of novel antitumor agents from mixture-based synthetic combinatorial libraries using cell-based assays

Area of Science:

• Drug Discovery and Development
• Oncology
• Medicinal Chemistry

Background:

• The search for novel antitumor agents is ongoing.
• Combinatorial library technology offers a vast source of potential drug candidates.
• High-throughput screening systems are crucial for efficient identification of active compounds.

Purpose of the Study:

• To present a new strategy integrating combinatorial library technology with an in vitro antitumor screening system.
• To identify novel antitumor agents from mixture-based synthetic combinatorial libraries (SCLs).
• To demonstrate the utility of cell-based assays for identifying lead compounds from SCLs.

Main Methods:

• Screening of mixture-based SCLs against a panel of 60 human tumor cell lines.
• Deconvolution of active SCLs to identify individual compounds.
• In vivo testing of active compounds, including maximum tolerated dose determination and hollow fiber assays.

Main Results:

• Five different SCLs were initially screened, with two (N-perbenzylated pentamine and N-acylated permethylated triamine) showing significant activity.
• Deconvolution yielded individual compounds with potent antitumor activity against the 60 cell lines.
• Three compounds identified through this strategy are currently undergoing evaluation in human tumor xenografts.

Conclusions:

• The presented strategy effectively utilizes in vitro cell-based assays to identify antitumor lead compounds from mixture-based combinatorial libraries.
• This approach accelerates the discovery of novel anticancer agents.
• The identified compounds show promise for further clinical development.