Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression.
Animals
Apoptosis
/ drug effects
Apoptosis Regulatory Proteins
/ genetics
Cell Line, Tumor
Cell Proliferation
/ drug effects
Drug Design
Humans
Indoles
/ pharmacology
Leukemia
/ drug therapy
Mice
Proteolysis
Proto-Oncogene Proteins
/ genetics
Proto-Oncogene Proteins c-mdm2
/ antagonists & inhibitors
Spiro Compounds
/ pharmacology
Tumor Suppressor Protein p53
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
24 01 2019
24 01 2019
Historique:
pubmed:
12
12
2018
medline:
29
10
2019
entrez:
12
12
2018
Statut:
ppublish
Résumé
Human murine double minute 2 (MDM2) protein is a primary endogenous cellular inhibitor of the tumor suppressor p53 and has been pursued as an attractive cancer therapeutic target. Several potent, nonpeptide, small-molecule inhibitors of MDM2 are currently in clinical development. In this paper, we report our design, synthesis, and evaluation of small-molecule MDM2 degraders based on the proteolysis targeting chimera (PROTAC) concept. The most promising compound (MD-224) effectively induces rapid degradation of MDM2 at concentrations <1 nM in human leukemia cells. It achieves an IC
Identifiants
pubmed: 30525597
doi: 10.1021/acs.jmedchem.8b00909
pmc: PMC6545112
mid: NIHMS1020015
doi:
Substances chimiques
4-(6''-chloro-4'-(3-chloro-2-fluorophenyl)-2''-oxodispiro(cyclohexane-1,2'-pyrrolidine-3',3''-indoline)-5'-carboxamido)benzoic acid
0
Apoptosis Regulatory Proteins
0
BBC3 protein, human
0
Indoles
0
Proto-Oncogene Proteins
0
Spiro Compounds
0
Tumor Suppressor Protein p53
0
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
448-466Subventions
Organisme : NCI NIH HHS
ID : P30 CA046592
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA208267
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA219345
Pays : United States
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