title: Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization.
abstract: Activation 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.
authors: Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. bradford.graves@roche.com
authors: Bradford
authors: B
authors: Graves
authors: Thelma
authors: T
authors: Thompson
authors: Mingxuan
authors: M
authors: Xia
authors: Cheryl
authors: C
authors: Janson
authors: Christine
authors: C
authors: Lukacs
authors: Dayanand
authors: D
authors: Deo
authors: Paola
authors: P
authors: Di Lello
authors: David
authors: D
authors: Fry
authors: Colin
authors: C
authors: Garvie
authors: Kuo-Sen
authors: KS
authors: Huang
authors: Lin
authors: L
authors: Gao
authors: Christian
authors: C
authors: Tovar
authors: Allen
authors: A
authors: Lovey
authors: Jutta
authors: J
authors: Wanner
authors: Lyubomir T
authors: LT
authors: Vassilev
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D003460:Crystallization; D019281:Dimerization; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D006827:Hydantoins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C022616:thiazolyl blue