Design and biological characterization of glioblastoma-effective senotherapeutics acting through Michael addition

• hlavní řešitel na UHK: RNDr. Patrik Olekšák, PhD., Katedra chemie PřF UHK
• hlavní řešitel: MUDr. Zdeněk Hodný, CSc., Ústav molekulární genetiky AV ČR, v.v.i.
• spoluřešitel: Mgr. Marie Vajrychová, Ph.D., Fakultní nemocnice Hradec Králové
• období řešení: 01/2026-12/2028
• reg. číslo: 26-21040S
• typ projektu: Standardní projekty GA ČR

The presence of senescent cells in glioblastoma (GB) is an adverse prognostic marker. Adjuvant senolytic therapy is one of the new, intensively investigated approaches for cancer treatment. In our previous work, we prepared and characterized a new compound, methoxybenzylaminobenzothiophene dioxide (K2071), which exhibits STAT3 inhibitory, antimitotic, anti-migratory, anti-invasive, and senotherapeutic properties. We hypothesize that the mechanism of action of K2071 involves covalent binding to an as-yet unidentified molecular target(s) via a thia-Michael addition. Our pilot findings suggest that further derivatization of K2071 can separate its antimitotic and senotherapeutic effects. In this proposal, we aim to develop novel GB-effective K2071 derivatives with enhanced senolytic and senomorphic properties. Using 2D and 3D in vitro culture models of human GB cell lines, we intend to elucidate their mechanisms of action, potential resistance, and synergies with other senolytics.