Use of Large Combinatorial Chemical Libraries for Anticancer Drug Discovery

Abstract

A new technology for drug discovery (Selectide technology) has been developed which greatly extends the capability for rapid molecular and cellular screening to large libraries containing millions of chemically synthesized compounds. Using a split synthesis approach to condensation chemistry, we recognized that each individual compound of potential interest is located on a different solid phase resin bead. Screening for binding activity on the bead surface: In order to screen for biological activity, we used several cleavable linkers which could release a portion of the compound from each bead into the solution phase in each of two sequential steps. For libraries comprised of peptides, there is sufficient residual peptide on each bead to permit sequence determination via Edman degradation. For non-peptide libraries, a system of peptide encoding is used on each bead so that the structure of the non-peptide compound can be determined by decoding the information conveyed by the peptide (which can be sequenced). We have applied this technology to various areas of drug discovery including a major interest in the development of anticancer drugs. Molecular targets under evaluation include cell surface monoclonal immunoglobulin on B-cell lymphomas, the epidermal growth factor receptor, and the HER2-neu receptor. Solution phase screening with releasable libraries is being used to evaluate anti-tumor activity using a battery of human tumor cell lines. Based on data obtained thus far, we believe that the Selectide technology has the potential for discovering novel new anticancer drugs.

Keywords::

• Combinatorial chemistry
• peptides
• drug discovery
• cancer
• screening