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Photoactivation of MDM2 Inhibitors: Controlling Protein-Protein Interaction with Light

Hansen, M. J., Feringa, F. M., Kobauri, P., Szymanski, W., Medema, R. H. & Feringa, B. L., 17-Oct-2018, In : Journal of the American Chemical Society. 140, 41, p. 13136-13141 6 p.

Research output: Contribution to journalArticleAcademicpeer-review

Selectivity remains a major challenge in anticancer therapy, which potentially can be overcome by local activation of a cytotoxic drug. Such triggered activation can be obtained through modification of a drug with a photoremovable protecting group (PPG), and subsequent irradiation in the chosen place and time. Herein, the design, synthesis and biological evaluation is described of a photoactivatable MDM2 inhibitor, PPG-idasanutlin, which exerts no functional effect on cellular outgrowth, but allows for the selective, noninvasive activation of antitumor properties upon irradiation visible light, demonstrating activation with micrometer, single cell precision. The generality of this method has been demonstrated by growth inhibition of multiple cancer cell lines showing p53 stabilization and subsequent growth inhibition effects upon irradiation. Light activation to regulate protein-protein interactions between MDM2 and p53 offers exciting opportunities to control a multitude of biological processes and has the potential to circumvent common selectivity issues in antitumor drug development.

Original languageEnglish
Pages (from-to)13136-13141
Number of pages6
JournalJournal of the American Chemical Society
Volume140
Issue number41
Publication statusPublished - 17-Oct-2018

    Keywords

  • PHOTOREMOVABLE PROTECTING GROUPS, P53 PATHWAY, PRACTICAL SYNTHESIS, PHOTOPHARMACOLOGY, CYCLOADDITION, ACTIVATION, THERAPIES, STABILITY

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