Breast Cancer Drug Discovery with Combinatorial Chemical Libraries

摘要

Abstract using combinatorial chemistry, a library of non-peptidic compounds was developed for screening as potential anticancer agents. Several libraries were synthesized using a novel bead-linked adduct methodology. Over 4, 000 discrete compounds were synthesized and evaluated for growth inhibitory activity against a battery of ten established human tumor cell lines. Three compounds from two different libraries were highly potent (IC(sub 50) less than or equal to 10 nM) in this primary screen. One, derivative, compound A4, a was selectively cytotoxic in hormonally-dependent human ovary and breast cancer cell lines. Of three compounds advanced into the B-16 model (C57/bl mice), only A4 was active. It was shown to have activity against human MCF-7 breast cancer cells grown in SCID mice, and no hematologic or organ toxicities were observed. Mechanistic studies showed that the A4 compound inhibits DNA synthesis, but is not an intercalator. Cell killing was not schedule-dependent, but resulted in an accumulation of cells in S-phase of the cell cycle. A water soluble prodrug form of A4, BAMP-278 was synthesized and this agent was also active in human MCF-7 breast cancer cells in SCID mice. In summary, a new class of novel agents with breast cancer antitumor activity has been identified.