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

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 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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Neochoritis CG,Atmaj J,Twarda-Clapa A,Surmiak E,Skalniak L,Köhler LM,Muszak D,Kurpiewska K,Kalinowska-Tłuścik J,Beck B,Holak TA,Dömling A

doi

10.1016/j.ejmech.2019.111588

subject

Has Abstract

pub_date

2019-11-15 00:00:00

pages

111588

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)30722-6

journal_volume

182

pub_type

杂志文章

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