Milademetan
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Also known as Ds-3032DS3032aMdm2 inhibitor ds-3032RAIN-32
Summary
Milademetan (CHEMBL4292264) is a phase-3 clinical-stage small molecule targeting MDM2; indicated across 15 conditions including dedifferentiated liposarcoma and gastric adenocarcinoma.
At a glance
- Status: Max clinical phase 3 (not approved)
- Modality: Small molecule
- Targets: 1 (MDM2)
- Indications: 15 conditions
- Clinical trials: 10
- Chemistry: 618.5 Da · C30H34Cl2FN5O4
Identifiers
Drug identity and classification
| Field | Value |
|---|---|
| ChEMBL ID | CHEMBL4292264 |
| Name | Milademetan |
| Type | Small molecule |
| Max phase | 3 |
| FDA approved | no |
| PubChem CID | 73297272 |
| Molecular formula | C30H34Cl2FN5O4 |
| Molecular weight | 618.5 |
| InChIKey | RYAYYVTWKAOAJF-QISPRATLSA-N |
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
Also known as: Ds-3032, DS-3032, DS3032a, Mdm2 inhibitor ds-3032, Milademetan, RAIN-32, MILADEMETAN
Parent form; salt/anhydrous children: CHEMBL4297374
Patent coverage: 178 distinct patent families (466 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 451 (97%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.
Targets
Targets
Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).
| Gene | Target | Action | pAffinity | Cancer dependency | UniProt |
|---|---|---|---|---|---|
| MDM2 | MDM2 proto-oncogene | Binding | 8.25 | 38.4% | Q00987 |
Broader ChEMBL bioactivity targets: 2 (assay-derived). Sample: Tumour suppressor p53/oncoprotein Mdm2, E3 ubiquitin-protein ligase Mdm2.
Bioactivity
ChEMBL activities: 2 potent at pChembl ≥ 5 of 2 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):
| Target | pChembl | Type | Value | Unit | Activity ID |
|---|---|---|---|---|---|
| MDM2 | 8.25 | IC50 | 5.57 | nM | CHEMBL_ACT_18773016 |
| TP53 | 8.25 | IC50 | 5.57 | nM | CHEMBL_ACT_25878559 |
Target pathways
Aggregated over 1 target gene(s): MDM2.
Top Reactome pathways
48 total, by targets touching each:
| Pathway | Targets | Genes |
|---|---|---|
| Neurotransmitter receptors and postsynaptic signal transmission | 1 | MDM2 |
| Transmission across Chemical Synapses | 1 | MDM2 |
| Neuronal System | 1 | MDM2 |
| PIP3 activates AKT signaling | 1 | MDM2 |
| Signal Transduction | 1 | MDM2 |
| Cell Cycle | 1 | MDM2 |
| Disease | 1 | MDM2 |
| AKT phosphorylates targets in the cytosol | 1 | MDM2 |
| Generic Transcription Pathway | 1 | MDM2 |
| PI3K/AKT Signaling in Cancer | 1 | MDM2 |
| Cellular responses to stress | 1 | MDM2 |
| Oxidative Stress Induced Senescence | 1 | MDM2 |
| Cellular Senescence | 1 | MDM2 |
| Oncogene Induced Senescence | 1 | MDM2 |
| SUMOylation | 1 | MDM2 |
| SUMO E3 ligases SUMOylate target proteins | 1 | MDM2 |
| SUMOylation of transcription factors | 1 | MDM2 |
| SUMOylation of ubiquitinylation proteins | 1 | MDM2 |
| Transcriptional Regulation by TP53 | 1 | MDM2 |
| Metabolism of proteins | 1 | MDM2 |
| Trafficking of AMPA receptors | 1 | MDM2 |
| Glutamate binding, activation of AMPA receptors and synaptic plasticity | 1 | MDM2 |
| Regulation of TP53 Activity | 1 | MDM2 |
| Diseases of signal transduction by growth factor receptors and second messengers | 1 | MDM2 |
| Constitutive Signaling by AKT1 E17K in Cancer | 1 | MDM2 |
| Deubiquitination | 1 | MDM2 |
| Ub-specific processing proteases | 1 | MDM2 |
| Post-translational protein modification | 1 | MDM2 |
| Regulation of TP53 Activity through Phosphorylation | 1 | MDM2 |
| Regulation of TP53 Degradation | 1 | MDM2 |
Dominant GO biological processes
| GO term | Targets |
|---|---|
| negative regulation of transcription by RNA polymerase II | 1 |
| protein polyubiquitination | 1 |
| blood vessel development | 1 |
| blood vessel remodeling | 1 |
| regulation of heart rate | 1 |
| atrioventricular valve morphogenesis | 1 |
| endocardial cushion morphogenesis | 1 |
| ventricular septum development | 1 |
| atrial septum development | 1 |
| ubiquitin-dependent protein catabolic process | 1 |
| apoptotic process | 1 |
| traversing start control point of mitotic cell cycle | 1 |
| positive regulation of cell population proliferation | 1 |
| response to xenobiotic stimulus | 1 |
| response to toxic substance | 1 |
Indications & clinical
Indications
15 indications (0 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).
| Indication | Trial phase | MONDO | EFO |
|---|---|---|---|
| dedifferentiated liposarcoma | 3 | MONDO:0020563 | EFO:0003085 |
| gastric adenocarcinoma | 2 | MONDO:0005036 | EFO:0000503 |
| sarcoma | 2 | MONDO:0005089 | EFO:0000691 |
| melanoma | 2 | MONDO:0005105 | EFO:0000756 |
| ovarian carcinoma | 2 | MONDO:0005140 | EFO:0001075 |
| exocrine pancreatic carcinoma | 2 | MONDO:0005192 | EFO:0002618 |
| testicular cancer | 2 | MONDO:0005447 | EFO:0004281 |
| cholangiocarcinoma | 2 | MONDO:0019087 | EFO:0005221 |
| adrenal cortex carcinoma | 2 | MONDO:0006639 | EFO:1000796 |
| breast neoplasm | 2 | MONDO:0021100 | MONDO:0007254 |
| acute myeloid leukemia | 1 | MONDO:0018874 | EFO:0000222 |
| neoplasm | 1 | MONDO:0005070 | EFO:0000616 |
3 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.
Clinical trials
Total trials: 10.
Phase distribution
| Phase | Trials |
|---|---|
| PHASE1 | 5 |
| PHASE2 | 2 |
| PHASE3 | 1 |
| PHASE1/PHASE2 | 1 |
| EARLY_PHASE1 | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT04979442 | PHASE3 | TERMINATED | Treatment of Milademetan Versus Trabectedin in Patient With Dedifferentiated Liposarcoma |
| NCT05012397 | PHASE2 | TERMINATED | Milademetan in Advanced/Metastatic Solid Tumors |
| NCT05932667 | PHASE2 | TERMINATED | Milademetan and Fulvestrant in GATA3-mutant, ER+HER- Advanced or Metastatic Breast Cancer |
| NCT06090318 | PHASE1/PHASE2 | WITHDRAWN | Milademetan in Combination With Atezolizumab in Patients With Advanced Solid Tumors With CDKN2A Loss |
| NCT01877382 | PHASE1 | COMPLETED | A Multiple Ascending Dose Study of Milademetan in Subjects With Advanced Solid Tumors or Lymphomas |
| NCT02319369 | PHASE1 | TERMINATED | Safety, Tolerability and Pharmacokinetics of Milademetan Alone and With 5-Azacitidine (AZA) in Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS) |
| NCT03552029 | PHASE1 | TERMINATED | Milademetan Plus Quizartinib Combination Study in FLT3-ITD Mutant Acute Myeloid Leukemia (AML) |
| NCT03671564 | PHASE1 | COMPLETED | Study of Milademetan in Japanese Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) |
| NCT05758818 | PHASE1 | TERMINATED | A Study of Milademetan Administration on Cardiac Repolarization in Healthy Subjects |
| NCT03614455 | EARLY_PHASE1 | COMPLETED | Pharmacokinetics (PK) Drug Interaction Study of Milademetan and Itraconazole or Posaconazole in Healthy Participants |
Clinical evidence (CIViC)
No CIViC predictive evidence (expected for non-precision-medicine drugs).
Pharmacology
Pharmacogenomics
No PharmGKB pharmacogenomic data curated for this drug.
Related molecules
Related molecules
Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.
10 molecules share ≥1 primary target. Top 10 by shared-target count:
| Molecule | Source | Status | Shared targets |
|---|---|---|---|
| APOMORPHINE | ChEMBL | Phase 4 (approved) | MDM2 |
| CYTARABINE | ChEMBL | Phase 4 (approved) | MDM2 |
| NITROFURANTOIN | ChEMBL | Phase 4 (approved) | MDM2 |
| BRIGIMADLIN | ChEMBL | Phase 3 | MDM2 |
| IDASANUTLIN | ChEMBL | Phase 3 | MDM2 |
| NAVTEMADLIN | ChEMBL | Phase 3 | MDM2 |
| ALRIZOMADLIN | ChEMBL | Phase 2 | MDM2 |
| SIREMADLIN | ChEMBL | Phase 2 | MDM2 |
| THIRAM | ChEMBL | Phase 2 | MDM2 |
| Carfilzomib | PubChem | Approved | MDM2 |
Related Atlas pages
- Genes: MDM2
- Diseases: dedifferentiated liposarcoma
- Drugs: Apomorphine, Cytarabine, Nitrofurantoin, Brigimadlin, Idasanutlin, Navtemadlin, Carfilzomib