title: Inhibition of nutlin-resistant HDM2 mutants by stapled peptides.
abstract: Pharmacological modulation of p53 activity is an attractive therapeutic strategy in cancers with wild-type p53. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2, a key negative regulator of p53 and blocks its activity. We have described resistance mutations in HDM2 that selectively reduce affinity for Nutlin but not p53. In the present communication, we show that stapled peptides targeting the same region of HDM2 as Nutlin are refractory to these mutations, and display reduced discrimination between the wild-type and mutant HDM2s with regards to functional abrogation of interaction with p53. The larger interaction footprint afforded by stapled peptides suggests that this class of ligands may prove comparatively more resilient to acquired resistance in a clinical setting.
authors.affiliation: p53Lab, Agency for Science Technology and Research, Singapore, Singapore.
authors.forename: Siau Jia
authors.initials: SJ
authors.lastname: Wei
authors.forename: Thomas
authors.initials: T
authors.lastname: Joseph
authors.forename: Sharon
authors.initials: S
authors.lastname: Chee
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Larisa
authors.initials: L
authors.lastname: Yurlova
authors.forename: Kourosh
authors.initials: K
authors.lastname: Zolghadr
authors.forename: Christopher
authors.initials: C
authors.lastname: Brown
authors.forename: David
authors.initials: D
authors.lastname: Lane
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.forename: Farid
authors.initials: F
authors.lastname: Ghadessy
mesh_terms: D000818:Animals; D002460:Cell Line; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D055786:Gene Knockout Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D007093:Imidazoles; D008024:Ligands; D010455:Peptides; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2