Chemistry and Biology of a Series of Antitumor Sulfonamides

Exploiting Transcriptomic and Quantitative Proteomic Analyses for Exploring Druggable Chemical Space

Abstract

Sulfonamide-focused compound libraries have been synthesized in our laboratories for biological evaluation using antitumor phenotypic screens such as cancer cell proliferation assay, flow cytometric cell cycle analysis, and rat aorta tube formation assay. Among thousands of sulfonamide compounds evaluated, E7010 (a microtubule depolymerizing agent), E7070 (a G1 phase cell cycle inhibitor), and E7820 (an antiangiogenesis agent) have progressed to clinical trials, thereby demonstrating some objective responses in cancer patients so far. The sequential discovery of these drug candidates allowed us to carry out a research approach of forward chemical genetics, in which phenotypically bioactive compounds are selected from a large collection of small molecules and then utilized for understanding the functions of their protein partners and relevant biological pathways via target identification. This paper describes our attempt using oligonucleotide microarray and quantitative proteomic analyses not only for identifying drug targets and downstream pathways applicable to biomarkers but also for exploring druggable chemical space in medicinal chemistry research.