3W69

Crystal structure of human mdm2 with a dihydroimidazothiazole inhibitor

Summary for 3W69

• Entry DOI: 10.2210/pdb3w69/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (5R,6S)-2-[((2S,5R)-2-{[(3R)-4-acetyl-3-methylpiperazin-1-yl]carbonyl}-5-ethylpyrrolidin-1-yl)carbonyl]-5,6-bis(4-chlorophenyl)-3-isopropyl-6-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole, SULFATE ION, ... (4 entities in total)
• Functional Keywords: ubiquitin-protein ligase e3 mdm2, p53, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 2
• Total formula weight: 22091.59

Authors

Shimizu, H.,Katakura, S.,Miyazaki, M.,Naito, H.,Sugimoto, Y.,Kawato, H.,Okayama, T.,Soga, T. (deposition date: 2013-02-12, release date: 2013-06-05, Last modification date: 2023-11-08)

Primary citation

Miyazaki, M.,Naito, H.,Sugimoto, Y.,Yoshida, K.,Kawato, H.,Okayama, T.,Shimizu, H.,Miyazaki, M.,Kitagawa, M.,Seki, T.,Fukutake, S.,Shiose, Y.,Aonuma, M.,Soga, T.
Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors
Bioorg.Med.Chem., 21:4319-4331, 2013

PubMed Abstract: We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53.

PubMed: 23685175
DOI: 10.1016/j.bmc.2013.04.056

Experimental method

X-RAY DIFFRACTION (1.9 Å)