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MDM2 proto-oncogene

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Target id: 3136

Nomenclature: MDM2 proto-oncogene

Family: E3 ubiquitin ligase components

Contents:

Gene and Protein Information Click here for help
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 Click here for help
E3 ubiquitin-protein ligase Mdm2 | p53-binding protein Mdm2 | RING-type E3 ubiquitin transferase Mdm2
Database Links Click here for help
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 Click here for help
EC Number: 2.3.2.27

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
AMG-232 Small molecule or natural product Hs Inhibition 10.4 pKd 10
⤷ pKd 10.4 (Kd 4.5x10-11 M) [10]
Description: Binding affinity determined in a SPR assay, measuring inhibition of interaction between human p53 and recombinant MDM2.
JN122 Small molecule or natural product Hs Binding 9.1 pKi 2
⤷ pKi 9.1 (Ki 7x10-10 M) [2]
milademetan Small molecule or natural product Hs Binding 8.3 pIC50 3-4
⤷ pIC50 8.3 (IC50 5.57x10-9 M) [3-4]
RG7112 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Binding - - 11
⤷ [11]
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.

References

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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]

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