Nutlin-3a-aa: Improving the Bioactivity of a p53/MDM2 Interaction Inhibitor by Introducing a Solvent-Exposed Methylene Group

被引：3

作者：

Nietzold, Florian ^{[1
]}

Rubner, Stefan ^{[1
]}

Labuzek, Beata ^{[2
]}

Golik, Przemyslaw ^{[2
]}

Surmiak, Ewa ^{[2
]}

del Corte, Xabier ^{[2
,3
]}

Kitel, Radoslaw ^{[2
]}

Protzel, Christoph ^{[1
]}

Reppich-Sacher, Regina ^{[4
]}

Stichel, Jan ^{[4
]}

Magiera-Mularz, Katarzyna ^{[2
]}

Holak, Tad A. ^{[2
]}

Berg, Thorsten ^{[1
]}

机构：

[1] Univ Leipzig, Inst Organ Chem, Johannisallee 29, D-04103 Leipzig, Germany

[2] Jagiellonian Univ, Fac Chem, Dept Organ Chem, Gronostajowa 2, PL-30387 Krakow, Poland

[3] Univ Basque Country UPV EHU, Fac Farm, Ctr Invest & Estudios Avanzados Lucio Lascaray, Dept Quim Organ 1, Paseo Univ 7, Vitoria 01006, Spain

[4] Univ Leipzig, Inst Biochem, Bruderstr 34, D-04103 Leipzig, Germany

来源：

CHEMBIOCHEM | 2023年

关键词：

biological activity; drug design; inhibitors; protein structures; protein-protein interactions; EXOCYCLIC METHYLENE; MDM2; OPTIMIZATION; ANTAGONISTS; DISCOVERY; P53;

D O I：

10.1002/cbic.202300006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Nutlin-3a is a reversible inhibitor of the p53/MDM2 interaction. We have synthesized the derivative Nutlin-3a-aa bearing an additional exocyclic methylene group in the piperazinone moiety. Nutlin-3a-aa is more active than Nutlin-3a against purified wild-type MDM2, and is more effective at increasing p53 levels and releasing transcription of p53 target genes from MDM2-induced repression. X-ray analysis of wild-type MDM2-bound Nutlin-3a-aa indicated that the orientation of its modified piperazinone ring was altered in comparison to the piperazinone ring of MDM2-bound Nutlin-3a, with the exocyclic methylene group of Nutlin-3a-aa pointing away from the protein surface. Our data point to the introduction of exocyclic methylene groups as a useful approach by which to tailor the conformation of bioactive molecules for improved biological activity.

引用

页数：7

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