pki-587 and Uterine-Cervical-Neoplasms

This study describes the synthesis of novel 1,3,5-triazine derivatives as potent inhibitors of cervical cancer. The compounds were initially tested for inhibition of PI3K/mTOR, where they showed significant inhibitory activity. The top-ranking molecule (compound 6 h) was further tested against class I PI3K isoforms, such as PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ, where it showed the most significant activity against PI3Kα. Compound 6 h was then tested for anti-cancer activity against triple-negative breast cancer cells (MDA-MB321), human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human liver cancer cells (HepG2), and it showed the greatest potency against HeLa cells. The effects of compound 6 h were further evaluated against the HeLa cells, where it showed significant attenuation of cell viability by inducing cell cycle arrest in the G1 phase. Compound 6 h induced apoptosis and reduced migration and invasion of HeLa cells. Western blotting analysis showed that 6 h inhibited PI3K and mTOR with positive modulation of Bcl-2 and Bax levels in HeLa cells. The effects of compound 6 h were also investigated in a tumour xenograft mouse model, where it showed reduction of tumour volume and weight. It also inhibited the PI3K/Akt/mTOR signalling cascade in xenograft tumour tissues, as evidenced by western blotting analysis. The results of the present study suggest the possible utility of the designed 1,3,5-triazine derivative as a potent inhibitor of cervical cancer.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Triazines; Tumor Cells, Cultured; Uterine Cervical Neoplasms