European Journal of Medicinal Chemistry (2019)
Update date:2022-08-15
Topics: Targeting Experimental terms Chemical terms intrinsically disordered protein MDM2-p53 interaction on the move hitting
Neochoritis, Constantinos G.
Atmaj, Jack
Twarda-Clapa, Aleksandra
Surmiak, Ewa
Skalniak, Lukasz
K?hler, Lisa-Maria
Muszak, Damian
Kurpiewska, Katarzyna
Kalinowska-T?u?cik, Justyna
Beck, Barbara
Holak
D?mling, Alexander
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 α-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.
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