title: Ordering of the N-terminus of human MDM2 by small molecule inhibitors.
abstract: Restoration of p53 function through the disruption of the MDM2-p53 protein complex is a promising strategy for the treatment of various types of cancer. Here, we present kinetic, thermodynamic, and structural rationale for the remarkable potency of a new class of MDM2 inhibitors, the piperidinones. While these compounds bind to the same site as previously reported for small molecule inhibitors, such as the Nutlins, data presented here demonstrate that the piperidinones also engage the N-terminal region (residues 10-16) of human MDM2, in particular, Val14 and Thr16. This portion of MDM2 is unstructured in both the apo form of the protein and in MDM2 complexes with p53 or Nutlin, but adopts a novel β-strand structure when complexed with the piperidinones. The ordering of the N-terminus upon binding of the piperidinones extends the current model of MDM2-p53 interaction and provides a new route to rational design of superior inhibitors.
authors.affiliation: Molecular Structure & Characterization, Amgen, Inc., Thousand Oaks, California 91320, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Michelsen
authors.forename: John B
authors.initials: JB
authors.lastname: Jordan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lewis
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Long
authors.forename: Evelyn
authors.initials: E
authors.lastname: Yang
authors.forename: Yosup
authors.initials: Y
authors.lastname: Rew
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Peter
authors.initials: P
authors.lastname: Yakowec
authors.forename: Paul D
authors.initials: PD
authors.lastname: Schnier
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Leszek
authors.initials: L
authors.lastname: Poppe
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D010880:Piperidines; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2