Novel Pt(IV) complexes conjugated with the kinase inhibitors crizotinib or ceritinib were synthesized and assessed for anticancer activity. Cisplatin-derived derivatives bearing phenylbutyrate and either crizotinib (complex 3) or ceritinib (complex 7) exhibited the greatest efficacy and selectivity against cancer cells while sparing noncancerous counterparts. Both compounds maintained activity in three-dimensional spheroid models, where they reduced viability, inhibited migration, and suppressed invasive outgrowth. Cellular accumulation studies confirmed efficient uptake of 3 and 7. Mechanistic investigations revealed that crizotinib-containing complexes induced G2/M arrest, whereas ceritinib analogs, particularly 7, caused S-phase arrest and DNA damage responses. Moreover, both agents triggered apoptosis and hallmarks of immunogenic cell death, including calreticulin exposure, ATP and HMGB1 release, and enhanced phagocytosis by macrophages. These findings highlight complexes 3 and 7 as promising multifunctional candidates that combine cytotoxic, anti-invasive, and immune-activating properties, supporting Pt(IV)-kinase inhibitor conjugates as a potential strategy for targeted cancer chemotherapy.

Czech Academy of Sciences Institute of Biophysics Kralovopolska 135 CZ 61200 Brno Czech Republic

Department of Biophysics Faculty of Science Palacky University Slechtitelu 27 783 71 Olomouc Czech Republic

Faculty of Science Department of Biochemistry Masaryk University CZ 62500 Brno Czech Republic

Institute for Drug Research School of Pharmacy The Hebrew University of Jerusalem Jerusalem 9112102 Israel

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