HEMTAC WEE1 degrader-1 is a HSP90-mediated targeting chimera (HEMTAC) degrader of WEE1 ( HSP90 enzyme inhibitory activity is IC50: 16.76 nM). HEMTAC WEE1 degrader-1 promotes the ubiquitination and degradation of WEE1. HEMTAC WEE1 degrader-1 blocks the G2/M cell cycle. HEMTAC WEE1 degrader-1 has anticancer activity in acute myeloid leukemia (AML) patient-derived xenograft (PDX) models. HEMTAC WEE1 degrader-1 can be used in AML research. (Pink: HSP90 binder; Blue: WEE1 ligand; Black: linker) [1].
In Vivo, HEMTAC WEE1 degrader-1 (Compound 9c) (3 mg/kg, i.v., once every day for 4 weeks) has anticancer activity with minimal toxicity in a mouse AML patient-derived xenograft (PDX) model[1]. HEMTAC WEE1 degrader-1 (10 mg/kg, i.v., once every day for 3 d) has minimal myelosuppressive toxicity in healthy mice[1].
In Vitro, HEMTAC WEE1 degrader-1 (Compound 9c) (72 h) inhibits the proliferation activity of MV-4-11 cells (IC50: 8.08 nM) and primary AML cells (IC50: 4.77 nM)[1]. HEMTAC WEE1 degrader-1 (0.01-10 μM, 12 h) degrades WEE1 protein in MV-4-11 cells and has a minor effect on AKT protein, indicating that this effect is independent of HSP90 inhibition[1]. HEMTAC WEE1 degrader-1 (0.1-10 μM, 12 h) promotes the expression of WEE1 mRNA in MV-4-11 cells in a concentration-dependent manner[1]. HEMTAC WEE1 degrader-1 (3-30 nM, 72 h) induces cell cycle arrest at the G2/M phase of MV-4-11 cells in a concentration-dependent manner[1].
References:
[1]. Li X, et al. Design, synthesis and biological evaluation of WEE1 degraders via HSP90-mediated targeting chimeras for target therapy of acute myeloid leukemia. Eur J Med Chem. 2025 Jun 5;290:117512.
In Vivo, HEMTAC WEE1 degrader-1 (Compound 9c) (3 mg/kg, i.v., once every day for 4 weeks) has anticancer activity with minimal toxicity in a mouse AML patient-derived xenograft (PDX) model[1]. HEMTAC WEE1 degrader-1 (10 mg/kg, i.v., once every day for 3 d) has minimal myelosuppressive toxicity in healthy mice[1].
In Vitro, HEMTAC WEE1 degrader-1 (Compound 9c) (72 h) inhibits the proliferation activity of MV-4-11 cells (IC50: 8.08 nM) and primary AML cells (IC50: 4.77 nM)[1]. HEMTAC WEE1 degrader-1 (0.01-10 μM, 12 h) degrades WEE1 protein in MV-4-11 cells and has a minor effect on AKT protein, indicating that this effect is independent of HSP90 inhibition[1]. HEMTAC WEE1 degrader-1 (0.1-10 μM, 12 h) promotes the expression of WEE1 mRNA in MV-4-11 cells in a concentration-dependent manner[1]. HEMTAC WEE1 degrader-1 (3-30 nM, 72 h) induces cell cycle arrest at the G2/M phase of MV-4-11 cells in a concentration-dependent manner[1].
References:
[1]. Li X, et al. Design, synthesis and biological evaluation of WEE1 degraders via HSP90-mediated targeting chimeras for target therapy of acute myeloid leukemia. Eur J Med Chem. 2025 Jun 5;290:117512.