SZU-B6 is an orally active SIRT6 PROTAC degrader with DC50 values of 45 nM in SK-HEP-1 cells and 154 nM in Huh-7 cells, respectively. SZU-B6 mediates proteasome-dependent degradation of SIRT6 by recruiting the CRBN E3 ubiquitin ligase. SZU-B6 impairs DNA damage repair and promotes radiosensitization of cancer cells. SZU-B6 induces cell cycle arrest and apoptosis in cancer cells. SZU-B6 inhibits the proliferation of liver cancer cells. SZU-B6 suppresses the tumor growth of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in mice. SZU-B6 can be used in research related to hepatocellular carcinoma and intrahepatic cholangiocarcinoma [1] [2]. (Pink: SIRT6 ligand; Blue: Cereblon E3 ligase ligand; Black: linker ).
In Vivo, SZU-B6 (10 mg/kg; once every other day; for 4 consecutive weeks) inhibits hepatocellular carcinoma tumor growth in BALB/c nude mice with a T/C ratio of 39.6%. It also degrades SIRT6 in tumors, induces DNA damage and cell apoptosis, and no obvious toxicity is observed. In combination with Sorafenib and 3 Gy irradiation, it exerts a synergistic inhibitory effect on hepatocellular carcinoma tumor growth in BALB/c nude mice[1]. SZU-B6 (10 mg/kg; p.o.; 18 days) significantly inhibits tumor growth of intrahepatic cholangiocarcinoma in mice[2].
In Vitro, SZU-B6 (200-2000 nM; 36 h) induces dose-dependent degradation of SIRT6 in SK-HEP-1 cells. After 36 h of treatment, the degradation rate reaches 67.7% at 200 nM and 92.5% at 2 μM[1]. SZU-B6 (0-10 μM; 36 h) potently induces dose-dependent degradation of SIRT6 in Huh-7 cells, with a DC50 of 154.28 nM and a maximum degradation efficiency of 91.79%[1]. SZU-B6 (0.02-5 μM; 24-36 h) induces time- and dose-dependent selective degradation of SIRT6 in SK-HEP-1, Huh-7 and Hep3B cells[1]. SZU-B6 (2.5 μM; 36 h with 2 h pretreatment) induces SIRT6 degradation in SK-HEP-1 cells via a CRBN- and proteasome-dependent mechanism[1]. SZU-B6 (0-10 μM; 72 h) potently inhibits the proliferation of SK-HEP-1 cells with an IC50 of 1.51 μM; when combined with 3 Gy irradiation, its antiproliferative activity is significantly enhanced, with an IC50 of 0.45 μM after 72 h of treatment[1]. SZU-B6 (2.5 μM) inhibits colony formation in SK-HEP-1 and Huh-7 cells[1]. SZU-B6 (0.04-5 μM; 36 h) induces dose-dependent degradation of SIRT6 in SK-HEP-1 cells and impairs DNA damage repair function[1]. SZU-B6 (5 μM; administered 36 h prior to transfection) significantly inhibits the homologous recombination DNA double-strand break repair pathway in DR-U2OS cells and the non-homologous end joining DNA double-strand break repair pathway in EJ5-U2OS cells, respectively[1]. SZU-B6 (5 μM; administered 36 h prior to 10 Gy irradiation) increases residual DNA damage in SK-HEP-1 cells after 10 Gy irradiation, as evidenced by longer comet tail moments following pretreatment with 5 μM for 36 h[1]. SZU-B6 (0-10 μM; 72 h) induces dose-dependent G2/M phase arrest and apoptosis in SK-HEP-1 cells[1].
References:
[1]. Huang J, et al. Discovery of Novel PROTAC SIRT6 Degraders with Potent Efficacy against Hepatocellular Carcinoma. Journal of medicinal chemistry. 2024 Oct 10;67(19):17319-17349.
[2]. Zhang M, et al. SIRT6 promotes intrahepatic cholangiocarcinoma development by reprogramming glutamine metabolism via enhanced GLUL. Gut. 2026 Jun 09;75(7):1383-1396.
In Vivo, SZU-B6 (10 mg/kg; once every other day; for 4 consecutive weeks) inhibits hepatocellular carcinoma tumor growth in BALB/c nude mice with a T/C ratio of 39.6%. It also degrades SIRT6 in tumors, induces DNA damage and cell apoptosis, and no obvious toxicity is observed. In combination with Sorafenib and 3 Gy irradiation, it exerts a synergistic inhibitory effect on hepatocellular carcinoma tumor growth in BALB/c nude mice[1]. SZU-B6 (10 mg/kg; p.o.; 18 days) significantly inhibits tumor growth of intrahepatic cholangiocarcinoma in mice[2].
In Vitro, SZU-B6 (200-2000 nM; 36 h) induces dose-dependent degradation of SIRT6 in SK-HEP-1 cells. After 36 h of treatment, the degradation rate reaches 67.7% at 200 nM and 92.5% at 2 μM[1]. SZU-B6 (0-10 μM; 36 h) potently induces dose-dependent degradation of SIRT6 in Huh-7 cells, with a DC50 of 154.28 nM and a maximum degradation efficiency of 91.79%[1]. SZU-B6 (0.02-5 μM; 24-36 h) induces time- and dose-dependent selective degradation of SIRT6 in SK-HEP-1, Huh-7 and Hep3B cells[1]. SZU-B6 (2.5 μM; 36 h with 2 h pretreatment) induces SIRT6 degradation in SK-HEP-1 cells via a CRBN- and proteasome-dependent mechanism[1]. SZU-B6 (0-10 μM; 72 h) potently inhibits the proliferation of SK-HEP-1 cells with an IC50 of 1.51 μM; when combined with 3 Gy irradiation, its antiproliferative activity is significantly enhanced, with an IC50 of 0.45 μM after 72 h of treatment[1]. SZU-B6 (2.5 μM) inhibits colony formation in SK-HEP-1 and Huh-7 cells[1]. SZU-B6 (0.04-5 μM; 36 h) induces dose-dependent degradation of SIRT6 in SK-HEP-1 cells and impairs DNA damage repair function[1]. SZU-B6 (5 μM; administered 36 h prior to transfection) significantly inhibits the homologous recombination DNA double-strand break repair pathway in DR-U2OS cells and the non-homologous end joining DNA double-strand break repair pathway in EJ5-U2OS cells, respectively[1]. SZU-B6 (5 μM; administered 36 h prior to 10 Gy irradiation) increases residual DNA damage in SK-HEP-1 cells after 10 Gy irradiation, as evidenced by longer comet tail moments following pretreatment with 5 μM for 36 h[1]. SZU-B6 (0-10 μM; 72 h) induces dose-dependent G2/M phase arrest and apoptosis in SK-HEP-1 cells[1].
References:
[1]. Huang J, et al. Discovery of Novel PROTAC SIRT6 Degraders with Potent Efficacy against Hepatocellular Carcinoma. Journal of medicinal chemistry. 2024 Oct 10;67(19):17319-17349.
[2]. Zhang M, et al. SIRT6 promotes intrahepatic cholangiocarcinoma development by reprogramming glutamine metabolism via enhanced GLUL. Gut. 2026 Jun 09;75(7):1383-1396.