<p>Structure-Based Discovery of Selective Histone Deacetylase 8 Degraders with Potent Anticancer Activity</p>

Huang, Jinbo; Zhang, Jun; Xu, Wenchao; Wu, Qiong; Zeng, Rongsheng; Liu, Zhichao; Tao, Wenhui; Chen, Qian; Wang, Yongqing; Zhu, Wei-Gu G

<p>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 (), which effectively induced HDAC8 protein degradation and inhibited cancer cell growth even at low micromolar concentrations. Our preliminary mechanistic studies revealed that hampers DNA damage repair in cancer cells, promoting cellular radiosensitization. In mice, a single dose induced rapid and prolonged HDAC8 protein degradation in xenograft tumor tissues. Moreover, 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.</p>

Structure-Based Discovery of Selective Histone Deacetylase 8 Degraders with Potent Anticancer Activity
Article (Faculty180)