HEMTACWEE1degrader-1 is a WEE1-targeting heterobifunctional chimeric degrader (HEMTAC) facilitated by HSP90, exhibiting an HSP90 enzyme inhibitory activity with an IC50 of 16.76 nM. It enhances the ubiquitination and subsequent degradation of WEE1, effectively blocking the G2/M cell cycle transition. This compound shows anticancer properties in patient-derived xenograft (PDX) models of acute myeloid leukemia (AML). HEMTACWEE1degrader-1 is utilized in AML research.

HSP90:16.76 nM

HEMTAC WEE1 degrader-1 (Compound 9c) effectively inhibits the proliferation of MV-4-11 cells (IC50: 8.08 nM) and primary AML cells (IC50: 4.77 nM) over 72 hours. Within a range of 0.01-10 μM over 12 hours, it degrades WEE1 protein in MV-4-11 cells with minimal impact on AKT protein, indicating action independent of HSP90 inhibition. Additionally, concentrations from 0.1-10 μM over 12 hours lead to a concentration-dependent increase in WEE1 mRNA expression in MV-4-11 cells. At concentrations of 3-30 nM over 72 hours, it induces G2/M phase cell cycle arrest in MV-4-11 cells in a concentration-dependent manner.

The compound HEMTAC WEE1 degrader-1 (Compound 9c), administered intravenously at a dose of 3 mg/kg once daily for four weeks, demonstrates anticancer efficacy with minimal toxicity in a mouse AML patient-derived xenograft (PDX) model. Additionally, in healthy mice, HEMTAC WEE1 degrader-1 (10 mg/kg, intravenously, once daily for three days) exhibits mild bone marrow suppression toxicity.