title: Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction.
abstract: We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be 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: John
authors.initials: J
authors.lastname: Eksterowicz
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
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: 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 B
authors.initials: JB
authors.lastname: Houze
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.forename: Yihong
authors.initials: Y
authors.lastname: Li
authors.forename: Zhihong
authors.initials: Z
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: Dustin L
authors.initials: DL
authors.lastname: McMinn
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: Julio C
authors.initials: JC
authors.lastname: Medina
authors.forename: Daqing
authors.initials: D
authors.lastname: Sun
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D007202:Indicators and Reagents; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009025:Morpholines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000588583:2-(4-(2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin-2-yl)acetic acid; D000085:Acetates; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D009025:Morpholines; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2