title: Novel inhibitors of the MDM2-p53 interaction featuring hydrogen bond acceptors as carboxylic acid isosteres.
abstract: We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.
authors.affiliation: Departments of Therapeutic Discovery, ‡Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Ana Z
authors.initials: AZ
authors.lastname: Gonzalez
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Li
authors.forename: Hilary P
authors.initials: HP
authors.lastname: Beck
authors.forename: Jude
authors.initials: J
authors.lastname: Canon
authors.forename: Ada
authors.initials: A
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Chow
authors.forename: Jason
authors.initials: J
authors.lastname: Duquette
authors.forename: John
authors.initials: J
authors.lastname: Eksterowicz
authors.forename: Brian M
authors.initials: BM
authors.lastname: Fox
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Fu
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Houze
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.forename: Yihong
authors.initials: Y
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Ling
authors.forename: Mei-Chu
authors.initials: MC
authors.lastname: Lo
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Long
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: McGee
authors.forename: Joel
authors.initials: J
authors.lastname: McIntosh
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Oliner
authors.forename: Tao
authors.initials: T
authors.lastname: Osgood
authors.forename: Yosup
authors.initials: Y
authors.lastname: Rew
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Saiki
authors.forename: Paul
authors.initials: P
authors.lastname: Shaffer
authors.forename: Sarah
authors.initials: S
authors.lastname: Wortman
authors.forename: Peter
authors.initials: P
authors.lastname: Yakowec
authors.forename: Xuelei
authors.initials: X
authors.lastname: Yan
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Ye
authors.forename: Dongyin
authors.initials: D
authors.lastname: Yu
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Steven H
authors.initials: SH
authors.lastname: Olson
authors.forename: Daqing
authors.initials: D
authors.lastname: Sun
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D012516:Osteosarcoma / Q000188:drug therapy; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C000589311:2-(2-(1-(2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)methyl)thiazol-5-yl)acetic acid; D000085:Acetates; D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D010881:Piperidones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2