milademetan   Click here for help

GtoPdb Ligand ID: 12941

Synonyms: DS-3032 | DS-3032B [3] | DS3032 | DS3032b | RAIN-32 [3]
Compound class: Synthetic organic
Comment: Milademetan (DS-3032) is an oral MDM2-p53 PPI inhibitor [2-3,6]. Based on evidence that inhibition of MDM2 can enhance p53 availability/function and potentiate cancer cell apoptosis, milademetan was developed as a potential cancer therapeutic [1-2,4].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Click here for structure editor
Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 9
Hydrogen bond donors 4
Rotatable bonds 5
Topological polar surface area 134.91
Molecular weight 618.53
XLogP 1.56
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES CC1(C)CCC2(CC1)[C@]3(C4=CC=C(C=C4NC3=O)Cl)[C@@H](C5=CC=NC(=C5F)Cl)[C@H](C(=O)N[C@@H]6CC[C@@H](C(=O)N)OC6)N2
Isomeric SMILES CC1(CCC2(CC1)[C@@]3([C@H]([C@@H](N2)C(=O)N[C@@H]4CC[C@H](OC4)C(=O)N)C5=C(C(=NC=C5)Cl)F)C6=C(C=C(C=C6)Cl)NC3=O)C
InChI InChI=1S/C30H34Cl2FN5O4/c1-28(2)8-10-29(11-9-28)30(18-5-3-15(31)13-19(18)37-27(30)41)21(17-7-12-35-24(32)22(17)33)23(38-29)26(40)36-16-4-6-20(25(34)39)42-14-16/h3,5,7,12-13,16,20-21,23,38H,4,6,8-11,14H2,1-2H3,(H2,34,39)(H,36,40)(H,37,41)/t16-,20+,21+,23-,30-/m1/s1
InChI Key RYAYYVTWKAOAJF-QISPRATLSA-N
References
1. Ananthapadmanabhan V, Frost TC, Soroko KM, Knott A, Magliozzi BJ, Gokhale PC, Tirunagaru VG, Doebele RC, DeCaprio JA. (2022)
Milademetan is a highly potent MDM2 inhibitor in Merkel cell carcinoma.
JCI Insight, 7 (13). [PMID:35801592]
2. Arnhold V, Schmelz K, Proba J, Winkler A, Wünschel J, Toedling J, Deubzer HE, Künkele A, Eggert A, Schulte JH et al.. (2018)
Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma.
Oncotarget, 9 (2): 2304-2319. [PMID:29416773]
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. Konopleva M, Martinelli G, Daver N, Papayannidis C, Wei A, Higgins B, Ott M, Mascarenhas J, Andreeff M. (2020)
MDM2 inhibition: an important step forward in cancer therapy.
Leukemia, 34 (11): 2858-2874. [PMID:32651541]
5. Koyama T, Shimizu T, Kojima Y, Sudo K, Okuma HS, Shimoi T, Ichikawa H, Kohsaka S, Sadachi R, Hirakawa A et al.. (2023)
Clinical Activity and Exploratory Resistance Mechanism of Milademetan, an MDM2 Inhibitor, in Intimal Sarcoma with MDM2 Amplification: An Open-Label Phase Ib/II Study.
Cancer Discov, 13 (8): 1814-1825. [PMID:37369013]
6. 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]
7. Sekiguchi N, Kasahara S, Miyamoto T, Kiguchi T, Ohno H, Takagi T, Tachibana M, Sumi H, Kakurai Y, Yamashita T et al.. (2023)
Phase I dose-escalation study of milademetan in patients with relapsed or refractory acute myeloid leukemia.
Int J Hematol, 117 (1): 68-77. [PMID:36258088]
8. Senapati J, Muftuoglu M, Ishizawa J, Abbas HA, Loghavi S, Borthakur G, Yilmaz M, Issa GC, Dara SI, Basyal M et al.. (2023)
A Phase I study of Milademetan (DS3032b) in combination with low dose cytarabine with or without venetoclax in acute myeloid leukemia: Clinical safety, efficacy, and correlative analysis.
Blood Cancer J, 13 (1): 101. [PMID:37386016]