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.