Design, synthesis, and screening of novel thienopyrimidine derivatives as PI3K/HDAC dual inhibitors against cervical cancer cells.

Phosphatidylinositol 3-kinase (PI3K) and histone deacetylase (HDAC) inhibition is a potential tumor treatment strategy, including for cervical cancer. Herein, a novel series of thienopyrimidine derivatives was rationally designed, synthesized, and biologically evaluated as dual PI3K/HDAC inhibitors targeting cervical cancer. Compound B7 was evaluated for its inhibitory effects across the entire PI3K and HDAC families, and exhibited strong PI3Kα (IC50 = 25.41 ± 5.23 nM), PI3Kδ (IC50 = 41.58 ± 4.54 nM), HDAC6 (IC50 = 29.35 ± 3.41 nM), and moderate HDAC8 inhibition (IC50 = 157.27 ± 6.18 nM). In cellular assays, B7 suppressed the proliferation of four cervical cancer cell lines (HeLa, SiHa, Ca-Ski, and ME-180) with IC50 values below 5 μM. And B7 showed moderate selectivity in normal L-O2 and HEK-293T cell viability with IC50 values around 15 μM. Mechanistically, B7 induced HeLa cell S-phase arrest and apoptosis. Notably, it blocked the PI3K/AKT pathway and upregulated α-tubulin and SMC3 acetylation without altering Ac-H3/H4 levels, consistent with its enzymatic selectivity for HDAC6/8 over Class I HDACs. Molecular dynamics simulations revealed that B7 formed stable binding modes with PI3Kα and HDAC6/8. Although rapid systemic clearance currently limits its in vivo application, the potent cellular efficacy of B7 highlights its utility as a dual PI3K/HDAC lead compound, providing a distinct chemical scaffold for further structural optimization.