Differential Targeting of Human Topoisomerase II Isoforms with Small Molecules

The TOP2 poison etoposide has been
implicated in the generation
of secondary malignancies during cancer treatment. Structural similarities
between TOP2 isoforms challenge the rational design of isoform-specific
poisons to further delineate these processes. Herein, we describe
the synthesis and biological evaluation of a focused library of etoposide
analogues, with the identification of two novel small molecules exhibiting
TOP2B-dependent toxicity. Our findings pave the way toward studying
isoform-specific cellular processes by means of small molecule intervention.