SZUH280 is a Potent And Selective PROTAC HDAC8 Degrader
Histone deacetylase 8 (HDAC8) is a class I histone deacetylase. Unlike other class I HDACs, it localizes both in the nucleus and in the cytoplasm. HDAC8 can also target non-histone proteins, such as the structural maintenance of chromosome 3 (SMC3) cohesin protein, retinoic acid induced 1 (RAI1) and p53. Thus, HDAC8 is a therapeutic target in various diseases, including cancer, X-linked intellectual disability, and parasitic infections. HDAC8 is either overexpressed or dysregulated in cancers, such as neuroblastoma, breast cancer, colon cancer and hematological malignancies.
Remarkable advances in targeted cancer therapy have been accomplished for the past several decades, and a number of targeted anticancer small-molecule drugs approved for the treatment of various types of cancer. Unlike conventional chemotherapeutics that non-specifically inhibit cell proliferation, a targeted cancer therapeutics suppresses cancer proliferation and progression by interacting with its protein of interest (POI) that cancer cells are heavily dependent on. PROTAC (PROteolysis-TArgeting Chimera) is a a useful technology for targeted protein degradation. PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the POI and a covalently linked ligand of an E3 ubiquitin ligase. Upon binding to POI, PROTACs can recruit E3 for POI ubiquitination, followed by degradation of POI by the proteasome system.
SZUH280 is a potent and selective PROTAC HDAC8 degrader.
CRBN SZUH280 induces E3 ubiquitin ligase-mediated HDAC8 degradation. SZUH280 inhibits A549 cell proliferation in a concentration-dependent manner and shows stronger antiproliferative effect with irradiation. Meanwhile, SZUH280 induces cancer cell Apoptosis. SZUH280 hampers DNA damage repair in cancer cells, promoting cellular radiosensitization. What’s more, SZUH280 can regulate the oncogenic protein expression and suppress cancer metastasis, potentially improving the efficacy of chemotherapy in various types of cancers. Besides, SZUH280 shows antitumor activity in an A549 nude mouse model.
All in all, SZUH280 is a potent and selective PROTAC HDAC8 degrader.
. Chakrabarti A, et, al. Trends Pharmacol Sci. 2015 Jul;36(7):481-92.