Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction

Neochoritis, Constantinos G.; Atmaj, Jack; Twarda-Clapa, Aleksandra; Surmiak, Ewa; Skalniak, Lukasz; Köhler, Lisa-Maria; Muszak, Damian; Kurpiewska, Katarzyna; Kalinowska-Tluscik, Justyna; Beck, Barbara; Holak, Tad A. und Domling, Alexander (2019): Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction. In: European Journal of Medicinal Chemistry, Bd. 182, 111588

Abstract

Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multistage process that amongst other, employs the dissociation of a transient alpha-helical N-terminal "lid" segment of MDM2 from the proximity of the p53-complementary interface. Several small molecule inhibitors have been reported to inhibit the formation of the p53-MDM2 complex with the vast majority mimicking the p53 residues Phe19, Trp23 and Leu26. Recently, we have described the transit from the 3-point to 4-point pharmacophore model stabilizing this intrinsically disordered N-terminus by increasing the binding affinity by a factor of 3. Therefore, we performed a thorough SAR analysis, including chiral separation of key compound which was evaluated by FP and 2D NMR. Finally, p53-specific anti-cancer activity towards p53-wild-type cancer cells was observed for several representative compounds. (C) 2019 Elsevier Masson SAS. All rights reserved.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0223-5234
• Sprache: Englisch