PROTAC RNF4 degrader-1 is a RNF4 PROTAC degrader ( K d = 64.5 nM) that degrades RNF4 via the ubiquitin-proteasome system. PROTAC RNF4 degrader-1 induces DNA damage, apoptosis, and exhibits antiproliferative activity in cancer cells. PROTAC RNF4 degrader-1 displays antitumor activity with no obvious side effects in mouse models. PROTAC RNF4 degrader-1 is applicable to the research of hepatocellular carcinoma [1]. (Pink: RNF4 ligand; Blue: VHL ligand; Black: linker).
In Vivo, PROTAC RNF4 degrader-1 (Compound RD12) (5-20 mg/kg; i.p.; once every two days; 20 days) induces significant dose-dependent hepatocellular carcinoma tumor growth inhibition in BALB/c nude mice, with 58% and 76% inhibition at 5 mg/kg and 20 mg/kg respectively, without causing observable liver toxicity or body weight loss[1].
In Vitro, PROTAC RNF4 degrader-1 (Compound RD12) (0.2-20 μM; 72 h) potently inhibits the proliferation of HepG2 human hepatocellular carcinoma cells with an IC50 of 0.48 μM[1]. PROTAC RNF4 degrader-1 (0.1-10 μM; 6 h) induces dose-dependent degradation of RNF4 protein in HepG2 human hepatocellular carcinoma cells[1]. PROTAC RNF4 degrader-1 (0-20 μM; 6 h) induces dose-dependent degradation of RNF4 protein in Huh7 human hepatocellular carcinoma cells with a DC50 of 4.16 μM[1]. PROTAC RNF4 degrader-1 (5 μM; 6 h after 2 h pre-incubation with MG132)-mediated RNF4 degradation in HepG2 and Huh7 human hepatocellular carcinoma cells is dependent on the ubiquitin-proteasome system, as pre-treatment with proteasome inhibitor MG132 reverses RNF4 loss[1]. PROTAC RNF4 degrader-1 (0.1-10 μM; 6 h) induces dose-dependent DNA damage in HepG2 and Huh7 human hepatocellular carcinoma cells, as measured by increased γH2AX levels[1]. PROTAC RNF4 degrader-1 (0-20 μM; 6 h) increases levels of RNF4 substrate proteins BRCA1 and MDC1 in a dose-dependent manner in Huh7 human hepatocellular carcinoma cells, consistent with RNF4 degradation[1]. PROTAC RNF4 degrader-1 (serial two-fold dilutions; 30 min at room temperature) binds directly to recombinant RNF4 protein with a Kd of 64.5 nM, as measured by MST[1]. PROTAC RNF4 degrader-1 (10 μM; 6 h) selectively induces degradation of RNF4 in Huh7 human hepatocellular carcinoma cells, with only 28 of 7483 identified proteins showing significant down-regulation[1]. PROTAC RNF4 degrader-1 (5 μM; 48 h) induces apoptosis in 52.1% of Huh7 human hepatocellular carcinoma cells[1].
References:
[1]. Wan H, et al. Development of the first-in-class RNF4 PROTAC degrader as potential therapeutics for hepatocellular carcinoma. Eur J Med Chem. 2026;307:118668.
In Vivo, PROTAC RNF4 degrader-1 (Compound RD12) (5-20 mg/kg; i.p.; once every two days; 20 days) induces significant dose-dependent hepatocellular carcinoma tumor growth inhibition in BALB/c nude mice, with 58% and 76% inhibition at 5 mg/kg and 20 mg/kg respectively, without causing observable liver toxicity or body weight loss[1].
In Vitro, PROTAC RNF4 degrader-1 (Compound RD12) (0.2-20 μM; 72 h) potently inhibits the proliferation of HepG2 human hepatocellular carcinoma cells with an IC50 of 0.48 μM[1]. PROTAC RNF4 degrader-1 (0.1-10 μM; 6 h) induces dose-dependent degradation of RNF4 protein in HepG2 human hepatocellular carcinoma cells[1]. PROTAC RNF4 degrader-1 (0-20 μM; 6 h) induces dose-dependent degradation of RNF4 protein in Huh7 human hepatocellular carcinoma cells with a DC50 of 4.16 μM[1]. PROTAC RNF4 degrader-1 (5 μM; 6 h after 2 h pre-incubation with MG132)-mediated RNF4 degradation in HepG2 and Huh7 human hepatocellular carcinoma cells is dependent on the ubiquitin-proteasome system, as pre-treatment with proteasome inhibitor MG132 reverses RNF4 loss[1]. PROTAC RNF4 degrader-1 (0.1-10 μM; 6 h) induces dose-dependent DNA damage in HepG2 and Huh7 human hepatocellular carcinoma cells, as measured by increased γH2AX levels[1]. PROTAC RNF4 degrader-1 (0-20 μM; 6 h) increases levels of RNF4 substrate proteins BRCA1 and MDC1 in a dose-dependent manner in Huh7 human hepatocellular carcinoma cells, consistent with RNF4 degradation[1]. PROTAC RNF4 degrader-1 (serial two-fold dilutions; 30 min at room temperature) binds directly to recombinant RNF4 protein with a Kd of 64.5 nM, as measured by MST[1]. PROTAC RNF4 degrader-1 (10 μM; 6 h) selectively induces degradation of RNF4 in Huh7 human hepatocellular carcinoma cells, with only 28 of 7483 identified proteins showing significant down-regulation[1]. PROTAC RNF4 degrader-1 (5 μM; 48 h) induces apoptosis in 52.1% of Huh7 human hepatocellular carcinoma cells[1].
References:
[1]. Wan H, et al. Development of the first-in-class RNF4 PROTAC degrader as potential therapeutics for hepatocellular carcinoma. Eur J Med Chem. 2026;307:118668.