The Acyl Sulfonamide Antiproliferatives and Other Novel Antitumor Agents

Publisher Summary This chapter discusses antiproliferative agents that are identified through general cytotoxic screening methods such as Lilly's acyl sulfonamide antiproliferative compound (ASAP) and Sunesis' SNS-595. ASAP compounds are observed to stimulate apoptosis. Because the compounds showed cellular activity at the outset, rapid optimization of the ASAP compounds is possible. The compounds are soluble in weakly basic bicarbonate buffer because of the acidity of the amide proton and are found to be highly stable to metabolism in liver microsomes. Thus, the medicinal chemistry efforts could be focused on optimizing potency and understanding the structure–activity relationships of the molecules rather than addressing physicochemical properties, permeability, and metabolic instability. SNS-595 is a 1,8-disubstituted naphthyridine. Data suggests that it causes selective double-strand breaks during deoxyribonucleic acid (DNA) synthesis. Many pathways exist to repair such damages; however, SNS-595 affects the DNA damage-sensing kinase (DNAPK) nonhomologous end-joining pathway. Even after the removal of SNS-595, cells could not repair the strand breaks, resulting ultimately in apoptosis. In the pre-clinical setting, toxicities are currently predicted by monitoring for weight loss (or death) in treated animals; however, the development of the Lilly ASAP series illustrates the use of counter-screening for selectivity versus normal fibroblasts.

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