ANGPT1-based targeted drug screening: Identification of Tasosartan and its activity against tyrosine kinase inhibitor resistance in chronic myeloid leukemia
Min Zhang, Ping Wang, Yunsheng Ran, Ruiyin Li, Junzhao Wan, Jianta Wang, Dan Ma, Ping LiuObjective
Chronic myeloid leukemia treatment is hampered by resistance to tyrosine kinase inhibitors, which is driven in part by the activation of JAK/STAT signaling mediated by intracellular angiopoietin-1 (ANGPT1). However, direct therapeutic strategies targeting this pathway remain unestablished.
Methods
We used computer-aided drug discovery to identify tasosartan as a small molecule targeting ANGPT1. Direct target engagement was validated using surface plasmon resonance and the cellular thermal shift assay.
Results
Functional assays demonstrated that tasosartan exhibited antileukemic activity in chronic myeloid leukemia cells overexpressing ANGPT1. In the tested cell models, tasosartan effectively inhibited leukemic cell proliferation and induced apoptosis; its mechanism of action involves inhibiting ANGPT1 expression and blocking the activation of the downstream JAK/STAT signaling pathway. In chronic myeloid leukemia cells with ANGPT1 overexpression and resistance to tyrosine kinase inhibitors, tasosartan also effectively suppressed cell proliferation under the experimental conditions. In an NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt xenograft model, tasosartan reduced the leukemic burden in chronic myeloid leukemia, thereby confirming its therapeutic potential through targeting ANGPT1.
Conclusion
Our findings demonstrate that intracellular ANGPT1 is a pharmacologically tractable target in chronic myeloid leukemia and that tasosartan serves as a proof-of-concept compound for inhibiting the ANGPT1–JAK/STAT axis. These findings suggest a potential strategy for treating ANGPT1-high, tyrosine kinase inhibitor-resistant chronic myeloid leukemia and provide a foundation for developing next-generation ANGPT1 inhibitors.