A novel hesperetin derivative DU12 targets cyclin-dependent kinase 17 (CDK17) to inhibit malignant progression of ovarian cancer

Ovarian Cancer is the most fatal gynecological malignancy, characterized by difficult early diagnosis, high invasiveness and metastasis, and frequent chemoresistance, highlighting an urgent need for targeted therapeutic agents with high efficacy and low toxicity. Hesperetin is a natural flavonoid with antitumor potential but limited activity and druggability. In this study, a novel hesperetin derivative DU12 was synthesized, and its anti-ovarian Cancer effects in vitro and in vivo as well as the underlying molecular mechanisms were systematically investigated. In vitro experiments demonstrated that DU12 concentration-dependently inhibited the proliferation, colony formation, migration, and invasion of SKOV3 and A2780 ovarian Cancer cells. Kinase profiling, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and molecular docking assays confirmed that cyclin-dependent kinase 17 (CDK17) is the direct target of DU12, and DU12 markedly suppressed CDK17 kinase activity. RNA Sequencing (RNA-seq) and functional assays revealed that DU12 downregulated the semaphorin 6C (SEMA6C)‑plexin A2 (PLXNA2) signaling pathway by targeting CDK17. Mechanistic studies suggested that CDK17 directly bound to SEMA6C and may maintain its protein stability by inhibiting K63-linked ubiquitination and degradation of SEMA6C, thereby promoting malignant progression of ovarian Cancer, The cytoplasmic domain of SEMA6C is the key core region responsible for its specific binding to CDK17. rescue experiments verified that the CDK17-SEMA6C-Plexin A2 axis is the key mediator of the anti-ovarian Cancer effects of DU12. In vivo nude mouse xenograft assays revealed that DU12 significantly suppressed tumor growth and downregulated the expression of CDK17, SEMA6C, and PLXNA2 in tumor tissues. Meanwhile, absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction and in vivo safety evaluation indicated that DU12 exhibited favorable water solubility, oral bioavailability, and plasma protein binding rate, with no obvious hepatorenal or hematologic toxicity at effective doses. Collectively, this study confirms that the hesperetin derivative DU12 inhibits ovarian Cancer proliferation and metastasis by targeting the CDK17-SEMA6C -Plexin A2 axis, with favorable bioactivity and safety, providing a novel candidate small-molecule drug and a new therapeutic target for ovarian Cancer.