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Gene and Protein Information | ||||||
Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | - | 491 | 12q15 | MDM2 | MDM2 proto-oncogene | |
Mouse | - | 489 | 10 66.32 cM | Mdm2 | transformed mouse 3T3 cell double minute 2 | |
Rat | - | 458 | 7q22 | Mdm2 | MDM2 proto-oncogene | |
Gene and Protein Information Comments | ||||||
Alternative splicing of the human gene results in a multitude of transcript variants and protein isoforms. Many of these isoforms have been detected only in tumour cells. |
Previous and Unofficial Names |
E3 ubiquitin-protein ligase Mdm2 | p53-binding protein Mdm2 | RING-type E3 ubiquitin transferase Mdm2 |
Database Links | |
Alphafold | Q00987 (Hs), P23804 (Mm) |
BRENDA | 2.3.2.27 |
ChEMBL Target | CHEMBL5023 (Hs), CHEMBL3600279 (Mm) |
Ensembl Gene | ENSG00000135679 (Hs), ENSMUSG00000020184 (Mm), ENSRNOG00000006304 (Rn), ENSMUSG00000020184 |
Entrez Gene | 4193 (Hs), 17246 (Mm), 314856 (Rn) |
Human Protein Atlas | ENSG00000135679 (Hs) |
KEGG Enzyme | 2.3.2.27 |
KEGG Gene | hsa:4193 (Hs), mmu:17246 (Mm), rno:314856 (Rn) |
OMIM | 164785 (Hs) |
Pharos | Q00987 (Hs) |
RefSeq Nucleotide | NM_002392 (Hs), NM_010786 (Mm), NM_001108099 (Rn) |
RefSeq Protein | NP_002383 (Hs), NP_034916 (Mm), NP_001101569 (Rn) |
UniProtKB | Q00987 (Hs), P23804 (Mm) |
Wikipedia | MDM2 (Hs) |
Enzyme Reaction | ||||
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Download all structure-activity data for this target as a CSV file
Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Inhibitor Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Aileron Therapeutics are developing an α-helical stapled peptide (ALRN-6924; structure not disclosed) that inhibits the interaction between wild type p53 and the p53 repressor proteins MDM2 and MDMX [7], with the hope that this mechanism will re-activate p53-mediated induction of tumour cell apoptosis [1,6]. Small molecule MDM2 inhibitors in clinical pipelines include idasanutlin (RG7388; Roche), milademetan (DS-3032; Rain Therapeutics/Daiichi Sankyo), siremadlin (HDM201; Novartis) and AMG-232 (Amgen). |
Biologically Significant Variant Comments |
Splice variants which don't contain p53 binding domain sequences are found in late-stage and high-grade ovarian and bladder carcinomas. |
General Comments |
MDM2 is a nuclear E3 ubiquitin-protein ligase. It can promote tumour formation by targeting the p53 tumour suppressor protein for proteasomal degradation [5,8-9]. MDM2 expression is regulated by p53 transcriptional activity. |
1. Carvajal LA, Neriah DB, Senecal A, Benard L, Thiruthuvanathan V, Yatsenko T, Narayanagari SR, Wheat JC, Todorova TI, Mitchell K et al.. (2018) Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci Transl Med, 10 (436). DOI: 10.1126/scitranslmed.aao3003 [PMID:29643228]
2. Cheng J, Yan Z, Jiang K, Liu C, Xu D, Lyu X, Hu X, Zhang S, Zhou Y, Li J et al.. (2023) Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein-Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy. J Med Chem, 66 (24): 16991-17025. [PMID:38062557]
3. da Mota VHS, Freire de Melo F, de Brito BB, da Silva FAF, Teixeira KN. (2022) Molecular docking of DS-3032B, a mouse double minute 2 enzyme antagonist with potential for oncology treatment development. World J Clin Oncol, 13 (6): 496-504. [PMID:35949428]
4. Liao G, Yang D, Ma L, Li W, Hu L, Zeng L, Wu P, Duan L, Liu Z. (2018) The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy. Eur J Med Chem, 159: 1-9. [PMID:30253242]
5. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell, 69 (7): 1237-45. [PMID:1535557]
6. Ng SY, Yoshida N, Christie AL, Ghandi M, Dharia NV, Dempster J, Murakami M, Shigemori K, Morrow SN, Van Scoyk A et al.. (2018) Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models. Nat Commun, 9 (1): 2024. [PMID:29789628]
7. Pairawan S, Zhao M, Yuca E, Annis A, Evans K, Sutton D, Carvajal L, Ren JG, Santiago S, Guerlavais V et al.. (2021) First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models. Breast Cancer Res, 23 (1): 29. [PMID:33663585]
8. Ries S, Biederer C, Woods D, Shifman O, Shirasawa S, Sasazuki T, McMahon M, Oren M, McCormick F. (2000) Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell, 103 (2): 321-30. [PMID:11057904]
9. Sasaki M, Kawahara K, Nishio M, Mimori K, Kogo R, Hamada K, Itoh B, Wang J, Komatsu Y, Yang YR et al.. (2011) Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11. Nat Med, 17 (8): 944-51. [PMID:21804542]
10. Sun D, Li Z, Rew Y, Gribble M, Bartberger MD, Beck HP, Canon J, Chen A, Chen X, Chow D et al.. (2014) Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem, 57 (4): 1454-72. [PMID:24456472]
11. Vu B, Wovkulich P, Pizzolato G, Lovey A, Ding Q, Jiang N, Liu JJ, Zhao C, Glenn K, Wen Y et al.. (2013) Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development. ACS Med Chem Lett, 4 (5): 466-9. [PMID:24900694]