SZUH280

SZUH280 is a potent and selective PROTAC HDAC8 degrader with a DC50 of 0.58 μM in A549 cells. SZUH280 induces cancer cell apoptosis. SZUH280 hampers DNA damage repair in cancer cells, promoting cellular radiosensitization[1].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA/RNA Synthesis

Signaling Pathways >> PROTAC >> PROTAC

Signaling Pathways >> Cell Cycle/DNA Damage >> HDAC

Signaling Pathways >> Epigenetics >> HDAC

HDAC8:0.58 μM (DC50)

HDAC8 degradation induced by SZUH280 (5 μM; 20 h) is mediated by the CRBN E3 ubiquitin ligase[1]. SZUH280 (0.1-10 μM; 20 h) can regulate the oncogenic protein expression and suppress cancer metastasis, potentially improving the efficacy of chemotherapy in various types of cancers[1]. SZUH280 (0-20 μM; 72 h) inhibits A549 cell proliferation in a concentration-dependent manner and shows stronger antiproliferative effect with irradiation[1]. SZUH280 (0-20 μM; 72 h) induces apoptosis and arrests cell cycle at G2/M phase in A549 cells[1]. SZUH280 (5 μM; 24 h) hampers DNA damage repair in cancer cells when in combination with irradiation[1]. Western Blot Analysis[1] Cell Line: A549, HCT116, HeLa and MDA-MB-231 cells Concentration: 0.1, 0.3, 1, 3 and 10 μM Incubation Time: 20 h Result: Efficiently induced HDAC8 degradation in a concentration-dependent manner in A549, HCT116 and HeLa cells. Reduced the IKZF1 protein levels to a lesser extent at 10 μM in A549 cells. Decreased PGM1 expression during glucose deprivation conditions in A549 cells. Decreased SMAD3 and HDAC8 protein levels in MDA-MB-231 cells. Cell Proliferation Assay[1] Cell Line: A549 cells Concentration: 2.5, 5, 10 and 20 μM Incubation Time: 72 h Result: Effectively inhibited cell proliferation in a concentration-dependent manner with an IC50 of 9.55 μM. Co-treatment with irradiation exhibited an even stronger antiproliferative effect (with an IC50 value of about 6.04 μM). Apoptosis Analysis[1] Cell Line: A549 cells Concentration: 1.25, 2.5, 5, 10 and 20 μM Incubation Time: 72 h Result: Effectively induced apoptosis in a dose-dependent manner. Cell Cycle Analysis[1] Cell Line: A549 cells Concentration: 1.25, 2.5, 5, 10 and 20 μM Incubation Time: 72 h Result: Induced cell cycle arrest at the G2/M phase.

SZUH280 (5 mg/kg; i.p.; every 5 days for 6 weeks) shows antitumor activity in an A549 nude mouse model[1]. Animal Model: NOD/SCID mice (severe combined immunodeficient mice), A549 model[1] Dosage: 5 mg/kg Administration: Intraperitoneal injection, every 5 days for 6 weeks Result: Exhibited a significantly greater anti-lung cancer activity in vivo than the control group. When in combination with 3 Gy irradiation, achieved a much stronger antitumor activity.

[1]. Huang J, et al. Structure-Based Discovery of Selective Histone Deacetylase 8 Degraders with Potent Anticancer Activity. J Med Chem. 2022 Dec 14.