The discovery of the AGK inhibitor offers a targeted intervention strategy for the treatment of triple-negative breast cancer

ABSTRACT: Triple-negative breast cancer (TNBC) is highly aggressive, with a poor prognosis for patients, highlighting an urgent need for the development of safe and effective targeted intervention strategies. Through studies on specimens and clinical cases from TNBC patients, we demonstrated that acylglycerol kinase (AGK) is a promising target with remarkable clinical translational potential. In this study, we identified the first AGK inhibitor P13, a flavonoid derivative, that selectively and covalently binds to the Cys72 residue of AGK. Our research revealed that P13 not only inhibits the kinase-dependent functions of AGK in synthesizing phosphatidic acid (PA) and lysophosphatidic acid (LPA), but also significantly blocks its kinase-independent function involving furnish the TIM22 complex. Treatment with P13 induces mitochondrial dysfunction in TNBC cells, leading to tumor cell proliferation inhibition and stemness depletion. We also carefully evaluated the lead compound P13, confirming its favorable bioavailability and safety. Furthermore, using PDX experiments, we demonstrated that P13, whether administered as a monotherapy or in combination with paclitaxel, significantly inhibits TNBC cell proliferation. These findings validate the promising clinical translational potential of developing small-molecule drugs targeting AGK, which is expected to provide new insights into the targeted therapy of TNBC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE343180 | GEO | 2026/10/18

REPOSITORIES: GEO