3u15 | pdb_00003u15
Structure of hDMX with Dimer Inducing Indolyl Hydantoin RO-2443
Structural highlights
Function[MDM4_HUMAN] Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.[1] [2] Publication Abstract from PubMedActivation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization.,Graves B, Thompson T, Xia M, Janson C, Lukacs C, Deo D, Di Lello P, Fry D, Garvie C, Huang KS, Gao L, Tovar C, Lovey A, Wanner J, Vassilev LT Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11788-93. Epub 2012 Jun 28. PMID:22745160[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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