title: A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction.
abstract: The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a nongenotoxic anticancer therapy. Here, we present the syntheses, activities, and crystal structures of two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now. In particular, the 6-chloroindole group does not occupy the usual Trp-23 pocket of Mdm2 but instead is engaged in dimerization. This entirely unique binding mode of the compounds opens new possibilities for optimization of the Mdm2-p53 interaction inhibitors.
authors.affiliation: Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Surmiak
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland.|Malopolska Centre of Biotechnology, Jagiellonian University , Gronostajowa 7a, 30-387 Krakow, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Twarda-Clapa
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland.|Malopolska Centre of Biotechnology, Jagiellonian University , Gronostajowa 7a, 30-387 Krakow, Poland.
authors.forename: Krzysztof M
authors.initials: KM
authors.lastname: Zak
authors.affiliation: Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Musielak
authors.affiliation: Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Marcin D
authors.initials: MD
authors.lastname: Tomala
authors.affiliation: Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kubica
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Grudnik
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland.|Malopolska Centre of Biotechnology, Jagiellonian University , Gronostajowa 7a, 30-387 Krakow, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Madej
authors.affiliation: Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Jablonski
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland.|Malopolska Centre of Biotechnology, Jagiellonian University , Gronostajowa 7a, 30-387 Krakow, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
authors.affiliation: Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Kalinowska-Tluscik
authors.affiliation: Faculty of Mathematics and Natural Sciences, Department of Pharmacy, University of Groningen , 9713AV Groningen, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dömling
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland.|Malopolska Centre of Biotechnology, Jagiellonian University , Gronostajowa 7a, 30-387 Krakow, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Dubin
authors.affiliation: Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.|Malopolska Centre of Biotechnology, Jagiellonian University , Gronostajowa 7a, 30-387 Krakow, Poland.
authors.forename: Tad A
authors.initials: TA
authors.lastname: Holak
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D060066:Protein Interaction Maps / Q000187:drug effects*; D055503:Protein Multimerization / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D011758:Pyrroles; D016159:Tumor Suppressor Protein p53; C004511:butenolide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D015107:4-Butyrolactone