5lav › Citations

Discovery of Novel Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2-p53 Interaction.

Gollner A, Rudolph D, Arnhof H, Bauer M, Blake SM, Boehmelt G, Cockroft XL, Dahmann G, Ettmayer P, Gerstberger T, Karolyi-Oezguer J, Kessler D, Kofink C, Ramharter J, Rinnenthal J, Savchenko A, Schnitzer R, Weinstabl H, Weyer-Czernilofsky U, Wunberg T, McConnell DB
J Med Chem 59 10147-10162 (2016)
Related entries: 5law, 5lay, 5laz

Cited: 25 times
EuropePMC logo PMID: 27775892

Abstract

Scaffold modification based on Wang's pioneering MDM2-p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro[3H-indole-3,3'-pyrrolidin]-2(1H)-one scaffold. Further structure-based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein-protein interaction (PPI) with TP53. The compounds are highly selective and show in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for 4-[(3S,3'S,3'aS,5'R,6'aS)-6-chloro-3'-(3-chloro-2-fluorophenyl)-1'-(cyclopropylmethyl)-2-oxo-1,2,3',3'a,4',5',6',6'a-octahydro-1'H-spiro[indole-3,2'-pyrrolo[3,2-b]pyrrole]-5'-yl]benzoic acid (BI-0252).

Articles - 5lav mentioned but not cited (1)

  1. Absolute Binding Free Energy Calculations for Highly Flexible Protein MDM2 and Its Inhibitors. Singh N, Li W. Int J Mol Sci 21 E4765 (2020)


Reviews citing this publication (7)

  1. Recent Small-Molecule Inhibitors of the p53-MDM2 Protein-Protein Interaction. Beloglazkina A, Zyk N, Majouga A, Beloglazkina E. Molecules 25 E1211 (2020)
  2. Decoding the messaging of the ubiquitin system using chemical and protein probes. Henneberg LT, Schulman BA. Cell Chem Biol 28 889-902 (2021)
  3. Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications. Zhong Q, Xiao X, Qiu Y, Xu Z, Chen C, Chong B, Zhao X, Hai S, Li S, An Z, Dai L. MedComm (2020) 4 e261 (2023)
  4. Therapeutic Strategies to Activate p53. Aguilar A, Wang S. Pharmaceuticals (Basel) 16 24 (2022)
  5. Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs That Enable Degradation. Márquez-Cantudo L, Ramos A, Coderch C, de Pascual-Teresa B. Molecules 26 5606 (2021)
  6. 2-Oxindole and related heterocycles: synthetic methodologies for their natural products and related derivatives. Sharma S, Monga Y, Gupta A, Singh S. RSC Adv 13 14249-14267 (2023)
  7. Synthesis of MDM2-p53 Inhibitor BI-0282 via a Dipolar Cycloaddition and Late-Stage Davis-Beirut Reaction. Ramharter J, Kulhanek M, Dettling M, Gmaschitz G, Karolyi-Oezguer J, Weinstabl H, Gollner A. Org Process Res Dev 26 2526-2531 (2022)

Articles citing this publication (17)



Quick links