Inhibiting Hdm2 and ubiquitin-activating enzyme: targeting the ubiquitin conjugating system in cancer.
The ubiquitin conjugating system represents a rich source of potential molecular targets for cancer and other diseases. One target of great interest is the RING finger ubiquitin ligase (E3) Hdm2/Mdm2, which is frequently overexpressed in cancer and is a critical E3 for the tumor suppressor p53. For those 50% of tumors that express wild-type p53, agents that inhibit Hdm2 have great potential clinical utility. We summarize our ongoing efforts to identify inhibitors of Hdm2 E3 activity by high-throughput screening of both defined small molecules and natural product extracts. Employing a strategy using both enzymatic and cell-based assays, we have identified inhibitors that block the E3 activity of Hdm2, activate a p53 response, preferentially kill p53-expressing cells, and have the capacity to differentially cause death of transformed cells. Therefore, screening for inhibitors of Hdm2 ubiquitin ligase activity through in vitro assays represents a powerful means of identifying molecules that activate p53 in cancer cells to induce apoptosis. We also discuss the potential of inhibitors of ubiquitin-activating enzyme (E1) that were discovered during these screens. E1 inhibitors may similarly serve as the basis for novel therapeutics. Additionally, they represent unique tools for providing new insights into the ubiquitin conjugating system.
Weissman
A M
AM
Laboratory of Protein Dynamics and Signaling, National Cancer Institute at Frederick, P.O. Box. Bldg. 560, Frederick, MD 21702-1201, USA. amw@nih.gov
Yang
Y
Y
Kitagaki
J
J
Sasiela
C A
CA
Beutler
J A
JA
O'Keefe
B R
BR
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000970:Antineoplastic Agents; D001688:Biological Products; D004791:Enzyme Inhibitors; D025801:Ubiquitin; D051736:Proto-Oncogene Proteins c-mdm2; D044764:Ubiquitin-Activating Enzymes