Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells.
The p53 tumor suppressor protein is regulated by its interaction with HDM2, which serves as a ubiquitin ligase (E3) to target p53 for degradation. We have identified a family of small molecules (HLI98) that inhibits HDM2's E3 activity. These compounds show some specificity for HDM2 in vitro, although at higher concentrations effects on unrelated RING and HECT domain E3s are detectable, which could be due, at least in part, to effects on E2-ubiquitin thiol-ester levels. In cells, the compounds allow the stabilization of p53 and HDM2 and activation of p53-dependent transcription and apoptosis, although other p53-independent toxicity was also observed.
Yang
Yili
Y
Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute at Frederick, NIH, 1050 Boyles Street, Frederick, MD 21702, USA.
Ludwig
Robert L
RL
Jensen
Jane P
JP
Pierre
Shervon A
SA
Medaglia
Maxine V
MV
Davydov
Ilia V
IV
Safiran
Yassamin J
YJ
Oberoi
Pankaj
P
Kenten
John H
JH
Phillips
Andrew C
AC
Weissman
Allan M
AM
Vousden
Karen H
KH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005415:Flavins / Q000737:chemistry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D000075702:Nedd4 Ubiquitin Protein Ligases; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000098563:Seven in Absentia Proteins
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056827:Endosomal Sorting Complexes Required for Transport; D004791:Enzyme Inhibitors; D005415:Flavins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C019319:5-deazaflavin; D000075702:Nedd4 Ubiquitin Protein Ligases; C471639:UBE3A protein, human; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D011065:Poly(ADP-ribose) Polymerases; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D020169:Caspases