72784-47-5Relevant articles and documents
Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction
Chessari, Gianni,Hardcastle, Ian R.,Ahn, Jong Sook,Anil, Burcu,Anscombe, Elizabeth,Bawn, Ruth H.,Bevan, Luke D.,Blackburn, Timothy J.,Buck, Ildiko,Cano, Celine,Carbain, Benoit,Castro, Juan,Cons, Ben,Cully, Sarah J.,Endicott, Jane A.,Fazal, Lynsey,Golding, Bernard T.,Griffin, Roger J.,Haggerty, Karen,Harnor, Suzannah J.,Hearn, Keisha,Hobson, Stephen,Holvey, Rhian S.,Howard, Steven,Jennings, Claire E.,Johnson, Christopher N.,Lunec, John,Miller, Duncan C.,Newell, David R.,Noble, Martin E. M.,Reeks, Judith,Revill, Charlotte H.,Riedinger, Christiane,St. Denis, Jeffrey D.,Tamanini, Emiliano,Thomas, Huw,Thompson, Neil T.,Vinkovi?, Mladen,Wedge, Stephen R.,Williams, Pamela A.,Wilsher, Nicola E.,Zhang, Bian,Zhao, Yan
supporting information, p. 4071 - 4088 (2021/05/04)
Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.
Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298)
Soares, Pedro,Gadd, Morgan S.,Frost, Julianty,Galdeano, Carles,Ellis, Lucy,Epemolu, Ola,Rocha, Sonia,Read, Kevin D.,Ciulli, Alessio
, p. 599 - 618 (2018/02/07)
The von Hippel-Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants 100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways and new VHL ligands for next-generation PROTACs.
NOVEL COMPOUNDS
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Page/Page column 117, (2014/10/03)
The present invention relates substituted N-biphenyl-3-acetylamino-benzamides and N-[3-(acetylamino)phenyl]-biphenyl-carboxamides of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative disorder, as a sole agent or in combination with other active ingredients.
