4LWT

The 1.6A Crystal Structure of Humanized Xenopus MDM2 with RO5027344

Summary for 4LWT

• Entry DOI: 10.2210/pdb4lwt/pdb
• Related: 4LWU 4LWV
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (3S)-3-[(3R)-1-acetylpiperidin-3-yl]-6-chloro-3-(3-chlorobenzyl)-1,3-dihydro-2H-indol-2-one, SULFATE ION, ... (4 entities in total)
• Functional Keywords: mdm2, indolinone, e3 ubiquitin ligase, p53, nucleus, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Xenopus laevis (clawed frog,common platanna,platanna)
• Cellular location: Nucleus, nucleoplasm (By similarity): P56273
• Total number of polymer chains: 1
• Total formula weight: 10476.01

Authors

Graves, B.J.,Lukacs, C.,Kammlott, U. (deposition date: 2013-07-28, release date: 2014-07-16, Last modification date: 2024-02-28)

Primary citation

Zhang, Z.,Ding, Q.,Liu, J.J.,Zhang, J.,Jiang, N.,Chu, X.J.,Bartkovitz, D.,Luk, K.C.,Janson, C.,Tovar, C.,Filipovic, Z.M.,Higgins, B.,Glenn, K.,Packman, K.,Vassilev, L.T.,Graves, B.
Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy.
Bioorg.Med.Chem., 22:4001-4009, 2014

PubMed Abstract: The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994.

PubMed: 24997575
DOI: 10.1016/j.bmc.2014.05.072

Experimental method

X-RAY DIFFRACTION (1.6 Å)