Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction.
Antineoplastic Agents
/ chemical synthesis
Benzylamines
/ chemical synthesis
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cyanides
/ chemical synthesis
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Formates
/ chemical synthesis
Humans
Indoles
/ chemical synthesis
Intrinsically Disordered Proteins
/ antagonists & inhibitors
Molecular Structure
Proto-Oncogene Proteins c-mdm2
/ antagonists & inhibitors
Structure-Activity Relationship
Tumor Suppressor Protein p53
/ antagonists & inhibitors
(1)H–(15)N 2D HSQC NMR
4-Point pharmacophore model
AnchorQuery
Cancer
Intrinsically disordered proteins
SAR analysis
Ugi reaction
p53-MDM2
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
15 Nov 2019
15 Nov 2019
Historique:
received:
08
05
2019
revised:
22
07
2019
accepted:
04
08
2019
pubmed:
20
8
2019
medline:
22
11
2019
entrez:
18
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31421630
pii: S0223-5234(19)30722-6
doi: 10.1016/j.ejmech.2019.111588
pmc: PMC7008132
mid: NIHMS1066795
pii:
doi:
Substances chimiques
6-chloroindole
0
Antineoplastic Agents
0
Benzylamines
0
Cyanides
0
Formates
0
Indoles
0
Intrinsically Disordered Proteins
0
Tumor Suppressor Protein p53
0
formic acid
0YIW783RG1
MDM2 protein, human
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
111588Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM097082
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Masson SAS. All rights reserved.
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