6I3S
Crystal structure of MDM2 in complex with compound 13.
Summary for 6I3S
| Entry DOI | 10.2210/pdb6i3s/pdb |
| Descriptor | E3 ubiquitin-protein ligase Mdm2, (3~{S},3'~{R},3'~{a}~{S},6'~{a}~{R})-6-chloranyl-3'-(3-chloranyl-2-fluoranyl-phenyl)-1'-(cyclopropylmethyl)spiro[1~{H}-indole-3,2'-3~{a},6~{a}-dihydro-3~{H}-pyrrolo[3,4-b]pyrrole]-2,4'-dione, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | inhibitor, ligase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 11754.45 |
| Authors | Bader, G.,Kessler, D. (deposition date: 2018-11-07, release date: 2018-12-19, Last modification date: 2024-05-15) |
| Primary citation | Gollner, A.,Weinstabl, H.,Fuchs, J.E.,Rudolph, D.,Garavel, G.,Hofbauer, K.S.,Karolyi-Oezguer, J.,Gmaschitz, G.,Hela, W.,Kerres, N.,Grondal, E.,Werni, P.,Ramharter, J.,Broeker, J.,McConnell, D.B. Targeted Synthesis of Complex Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2-p53 Inhibitors. ChemMedChem, 14:88-93, 2019 Cited by PubMed Abstract: Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small-molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild-type tumors; however, it also revealed dose-limiting hematological toxicities and drug-induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less-frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro-oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96 . The designed molecules required the targeted synthesis of structurally complex spiro[indole-3,2'-pyrrolo[2,3-c]pyrrole]-2,4'-diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI-0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on-target adverse effects. PubMed: 30458062DOI: 10.1002/cmdc.201800617 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.77 Å) |
Structure validation
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