Tetracyclines as Antiproliferative Agents for Human Cancers

Abstract

In addition to their antimicrobial properties, the tetracycline class of natural products have demonstrated clinically important effects in the amelioration of human diseases, including cancer and mitochondrial disease. Previously, the Myers group utilized a multidisciplinary strategy featuring proteomics and photoaffinity labeling to identify the eukaryotic 80S ribosome as the target of the tetracyclines in human cells. Our group then established tetracycline derivatives doxycycline (1.4) and Col-3 (1.10) as inhibitors of cytosolic translation and activators of the general cellular stress monitor, the integrated stress response (ISR). Together, these efforts provided the crucial first steps in elucidating the mechanism by which the tetracyclines exert their antiproliferative effects. Since this initial discovery, our efforts to better understand the therapeutic potential of the tetracyclines have focused on two areas: novel compound synthesis and mechanistic elucidation. Early on, a medicinal chemistry campaign led to the discovery of a semisynthetic analogue of Col-3 (2.72) that displayed improved antiproliferative activity in several human cancer cell lines. We later transitioned to a fully synthetic strategy to enable access to a greater diversity of Col-3 analogues than was allowed by semisynthesis. These efforts resulted in the discovery of a series of C7-methoxy-C8-alkylamino analogues (3.96) with improved translation inhibitory potency compared to Col-3. Finally, our mechanistic elucidation efforts focused on investigations of translation inhibition and signaling pathway activation using a variety of biochemical techniques including polysome profiling, in vitro translation experiments, and knockout generation using CRISPR/Cas-9 technology. Overall, our efforts aim to develop novel tetracycline therapeutics with well-defined activities in human cancer cells with the goal of progressing these compounds to the clinic.