Abstract 5746: Development of Pt-HDACi complexes to enhance potency and selectivity for advanced cancer therapy

Abstract Combining standard chemotherapy drugs with low doses of histone deacetylase inhibitors (HDACis) has emerged as a promising approach to enhance cancer treatment efficacy. Incorporation of HDACi onto the platinum (Pt) core as a non-leaving group may improve the potency and selectivity of the Pt anticancer drugs and maintain the synergistic effect. In the newly synthesized inhibitors, the linker domain was modified by including heterocyclic rings or amine groups. One or two amine groups were installed onto the aromatic ring in the protein recognition domain to build monodentate or bidental coordination sites to incorporate Pt. Four HDACi derivatives (L19, L20, L21, L22) were successfully synthesized and fully characterized. Pt-HDACi complexes were obtained by reacting K2PtCl4 with bidentate L19 and L20, and K[PtCl3(2-picoline)] with monodentate L21 and L22. Intermediates and final compounds were analyzed using mass spectrometry and NMR spectroscopy. The purity was confirmed by melting point measurement, analytical HPLC, and/or elemental analysis. Different bioassays, such as enzyme inhibition, cell viability studies with cell lines K562, HCT-116, and A549, and DNA binding assay, have been applied to evaluate their efficacy. All four derivatives and Pt-HDACi conjugates have shown promising enzyme inhibition and potent bioactivities. Particularly, L19 and L21 with a heterocyclic ring in the linker showed the highest potency, with IC50 values significantly lower than the FDA-approved Vorinostat and Panobinostat. Molecular docking studies further supported these findings by revealing stronger binding affinity towards the HDAC enzymes, demonstrating similar trend in inhibition and potency toward cancer treatment. Citation Format: Rabeya Bosri, Jayden Stahl, Nghia Tran, Chao Feng, Liang Xue, Qinliang Zhao. Development of Pt-HDACi complexes to enhance potency and selectivity for advanced cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5746.