title: Discovery of highly potent p53-MDM2 antagonists and structural basis for anti-acute myeloid leukemia activities.
abstract: The inhibition of p53-MDM2 interaction is a promising new approach to non-genotoxic cancer treatment. A potential application for drugs blocking the p53-MDM2 interaction is acute myeloid leukemia (AML) due to the occurrence of wild type p53 (wt p53) in the majority of patients. Although there are very promising preclinical results of several p53-MDM2 antagonists in early development, none of the compounds have yet proven the utility as a next generation anticancer agent. Herein we report the design, synthesis and optimization of YH239-EE (ethyl ester of the free carboxylic acid compound YH239), a potent p53-MDM2 antagonizing and apoptosis-inducing agent characterized by a number of leukemia cell lines as well as patient-derived AML blast samples. The structural basis of the interaction between MDM2 (the p53 receptor) and YH239 is elucidated by a co-crystal structure. YH239-EE acts as a prodrug and is the most potent compound that induces apoptosis in AML cells and patient samples. The observed superior activity compared to reference compounds provides the preclinical basis for further investigation and progression of YH239-EE.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , 3501 Fifth Avenue, Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Huang
authors.forename: Siglinde
authors.initials: S
authors.lastname: Wolf
authors.forename: Barbara
authors.initials: B
authors.lastname: Beck
authors.forename: Lisa-Maria
authors.initials: LM
authors.lastname: Köhler
authors.forename: Kareem
authors.initials: K
authors.lastname: Khoury
authors.forename: Grzegorz M
authors.initials: GM
authors.lastname: Popowicz
authors.forename: Sayed K
authors.initials: SK
authors.lastname: Goda
authors.forename: Marion
authors.initials: M
authors.lastname: Subklewe
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Twarda
authors.forename: Tad A
authors.initials: TA
authors.lastname: Holak
authors.forename: Alexander
authors.initials: A
authors.lastname: Dömling
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D016159:Tumor Suppressor Protein p53; C000593018:ethyl 3-(2-((tert-butylamino)-1-(N-(4-chlorobenzyl)formamido)-2-oxoethyl)-6-chloro-1H-indole-2-carboxylate; D051736:Proto-Oncogene Proteins c-mdm2