Investigation of the inhibitory mechanism of apomorphine against MDM2-p53 interaction.

Abstract:

:Mirror-image screening using d-proteins is a powerful approach to provide mirror-image structures of chiral natural products for drug screening. During the course of our screening study for novel MDM2-p53 interaction inhibitors, we identified that NPD6878 (R-(-)-apomorphine) inhibited both the native l-MDM2-l-p53 interaction and the mirror-image d-MDM2-d-p53 interaction at equipotent doses. In addition, both enantiomers of apomorphine showed potent inhibitory activity against the native MDM2-p53 interaction. In this study, we investigated the inhibitory mechanism of both enantiomers of apomorphine against the MDM2-p53 interaction. Achiral oxoapomorphine, which was converted from chiral apomorphines under aerobic conditions, served as the reactive species to form a covalent bond at Cys77 of MDM2, leading to the inhibitory effect against the binding to p53.

journal_name

Bioorg Med Chem Lett

authors

Ishiba H,Noguchi T,Shu K,Ohno H,Honda K,Kondoh Y,Osada H,Fujii N,Oishi S

doi

10.1016/j.bmcl.2017.03.082

subject

Has Abstract

pub_date

2017-06-01 00:00:00

pages

2571-2574

issue

11

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(17)30332-3

journal_volume

27

pub_type

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