Structure-Based Discovery of Selective Histone Deacetylase 8 Degraders with Potent Anticancer Activity

Inducing protein degradation by proteolysis targeting chimeras has gained tremendous momentum as a promising novel therapeutic strategy. Here, we report the design, synthesis, and biological characterization of highly potent proteolysis targeting chimeric small molecules targeting the epigenetic regulator histone deacetylase 8 (HDAC8). We developed potent and effective HDAC8 degraders, as exemplified by SZUH280 (16e), which effectively induced HDAC8 protein degradation and inhibited cancer cell growth even at low micromolar concentrations. Our preliminary mechanistic studies revealed that SZUH280 hampers DNA damage repair in cancer cells, promoting cellular radiosensitization. In mice, a single SZUH280 dose induced rapid and prolonged HDAC8 protein degradation in xenograft tumor tissues. Moreover, SZUH280 alone or in combination with irradiation resulted in long-lasting tumor regression in an A549 tumor mouse model. Our findings qualify a new chemical tool for HDAC8 knockdown and may lead to the development of a new class of cancer therapeutics.

Automated summary

This study reports the design and synthesis of highly potent proteolysis targeting chimeric small molecules that effectively induce the degradation of the epigenetic regulator histone deacetylase 8 (HDAC8). The small molecule SZUH280 was found to inhibit cancer cell growth by promoting HDAC8 protein degradation even at low concentrations. Mechanistic studies revealed that SZUH280 also hampers DNA damage repair, leading to increased cellular radiosensitization.