eng Oriental Scientific Publishing Company Biomedical and Pharmacology Journal 0974-6242 2026-03-20 19 1 282 291 10.13005/bpj/3352 70070 article Aryo Tedjo 1 Novi Yantih 3 Fadilah 2 Mohamad Rafi 4 Department of Medical Chemistry, Faculty of Medicine, Universitas Indonesia, Jalan Salemba Raya 6, Jakarta, Indonesia Doctoral Program in Pharmaceutical Sciences, Universitas Pancasila, Jalan Srengseng sawah, Jakarta, Indonesia Faculty of Pharmacy, Universitas Pancasila, Jalan Srengseng sawah, Jakarta, Indonesia Department of Chemistry, Faculty of Mathematics and Natural Sciences, IPB University, JalanTanjung Kampus IPB Dramaga, Bogor, Indonesia Breast cancer of the luminal subtype remains a major cause of morbidity and mortality among women worldwide, largely due to the development of resistance to endocrine therapies such as tamoxifen. One of the transcription factors involved in the proliferation of breast cancer cells is E2F2, whose activity is regulated by the CDK4/6–Rb complex. This study aimed to evaluate the potential of active compounds in the 75% ethanol extract of Annona muricata (soursop) leaves as CDK6 inhibitors and suppressors of E2F2 expression in MCF-7 breast cancer cells. LC–MS/MS analysis identified 152 unique compounds, most of which belonged to the acetogenin class. Activity prediction using SkelSpheres descriptors based on support vector regression (SVR) yielded an R²-testing value of 0.8925, indicating high predictive validity for CDK6 inhibitory activity. Several compounds, including annonacin, muricin D, and longifolicin, exhibited predicted IC₅₀ values below 1 µM. Molecular docking results showed strong affinity between acetogenins and CDK6, with rerank scores comparable to the reference ligand ribociclib. In vitro cytotoxicity testing demonstrated that the extract had an IC₅₀ value of 9.7 ppm against MCF-7 cells. Gene expression analysis using RT-qPCR revealed a significant reduction in E2F2 expression following extract treatment (0.5175 ± 0.1732) compared with the control group (1.0087 ± 0.1517; p = 0.000), comparable to the effect of tamoxifen. These findings suggest that acetogenins present in the 75% ethanol extract of A. muricata leaves possess potential as anticancer candidates by suppressing E2F2 expression, presumably through the inhibition of CDK6. https://biomedpharmajournal.org/vol19no1/acetogenin-rich-annona-muricata-leaf-extract-as-a-cdk6-inhibitor-and-e2f2-suppressor-in-mcf-7-breast-cancer-cells/ Annona muricata CDK6 inhibitor E2F2 expression In silico In vitro MCF-7 breast cancer