[CAS NO. 1398568-47-2] Milademetan
PRODUCTS SPECIFICATIONS [1398568-47-2]
DESCRIPTION [1398568-47-2]
Overview
| MDL | MFCD31692325 |
|---|---|
| Molecular Weight | 618.53 |
| Molecular Formula | C30H34Cl2FN5O4 |
| SMILES | O=C(NC1=CC(Cl)=CC=C21)[C@]32C4(CCC(C)(C)CC4)N[C@@H](C(N[C@@H]5CC[C@@H](C(N)=O)OC5)=O)[C@@H]3C6=CC=NC(Cl)=C6F |
1 Publications Citing Use of MCE
Summary
IC50 & Target
MDM2 [1] .
In Vitro
Milademetan (DS-3032) can stabilize
TP53
and selectively induce CDKNA1, BAX and MDM2 expression in neuroblastoma cells with wild-type
TP53
[3]
.
Milademetan (DS-3032b) treatment enhances
TP53
target gene expression and induces
G1 cell cycle arrest
, senescence and
apoptosis
[3]
.
Milademetan (DS-3032b, 0-2000 nM) treatment selectively inhibits viability, proliferation and migration of neuroblastoma cells with wildtype
TP53
independently of MYCN status
[4]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Cell Viability Assay [4]
| Cell Line: | SK-N-SH, SH-SY5Y, IMR32, IMR5 and LAN5 cell lines. |
| Concentration: | 0-2000 nM. |
| Incubation Time: | 24-72 h. |
| Result: |
Reduced viability in a dose- and time-dependent manner.
Exhibited IC50 values of 21.9 nM, 17.7 nM, 52.63 nM, 25.7 nM and 44.1 nM in SK-N-SH, SH-SY5Y, IMR32, IMR5 and LAN5 cell lines, respectively (72 h). |
In Vivo
Milademetan (DS-3032b, 50 mg/kg, oral gavage) delays tumor growth and improves survival in mice xenografted with neuroblastoma cells with functional
TP53
[4]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
| Animal Model: | SH-SY5Y xenograft tumors in nude mice [4] . |
| Dosage: | 50 mg/kg. |
| Administration: | Oral gavage for 30 consecutive days with an alternating schedule of 4 days of daily treatment with oral gavages followed by 2 days without treatment (4+2). |
| Result: |
Survival in the mouse cohort was significantly prolonged.
Reduced neuroblastoma xenograft tumor growth by activating TP53 signaling. |
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date | Phase |
|---|---|---|---|---|
| NCT03634228 | M.D. Anderson Cancer Center|National Cancer Institute (NCI) |
Acute Myeloid Leukemia|Recurrent Acute Myeloid Leukemia|Refractory Acute Myeloid Leukemia
|
December 17, 2018 | Phase 1|Phase 2 |
| NCT03552029 | Daiichi Sankyo, Inc. |
Acute Myeloid Leukemia
|
December 12, 2018 | Phase 1 |
| NCT02319369 | Daiichi Sankyo, Inc. |
Acute Myelogenous Leukemia|Myelodysplastic Syndrome
|
November 25, 2014 | Phase 1 |
| NCT03647202 | Daiichi Sankyo, Inc. |
Food Effects on Pharmacokinetics
|
August 16, 2018 | Early Phase 1 |
| NCT03614455 | Daiichi Sankyo, Inc. |
Pharmacokinetics
|
July 13, 2018 | Early Phase 1 |
| NCT01877382 | Daiichi Sankyo, Inc. |
Advanced Solid Tumor|Lymphoma
|
July 2013 | Phase 1 |
| NCT03671564 | Daiichi Sankyo Co., Ltd.|Daiichi Sankyo, Inc. |
Acute Myeloid Leukemia
|
August 23, 2018 | Phase 1 |
| NCT02579824 | M.D. Anderson Cancer Center|Daiichi Sankyo UK Ltd. |
Myeloma
|
August 30, 2016 | Phase 1 |
Appearance
Solid
Shipping
Room temperature in continental US; may vary elsewhere.
Storage
| Powder | -20°C | 3 years |
|---|---|---|
| 4°C | 2 years | |
| In solvent | -80°C | 6 months |
| -20°C | 1 month |
Solvent & Solubility
DMSO : 16.67 mg/mL ( 26.95 mM ; Need ultrasonic)
Stock Solutions
| Concentration Solvent Mass | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 1.6167 mL | 8.0837 mL | 16.1674 mL |
| 5 mM | 0.3233 mL | 1.6167 mL | 3.2335 mL |
| 10 mM | 0.1617 mL | 0.8084 mL | 1.6167 mL |
References
- [1] ARYL SULFONOHYDRAZIDES. WO 2017069289 A1.
- [2] M.M. Gounder, et al. Milademetan, an oral MDM2 inhibitor, in well-differentiated/dedifferentiated liposarcoma: results from a phase 1 study in patients with solid tumors or lymphomas. European Journal of Cancer 138S2 (2020) S1–S62.
- [3] Li, Yangbing, et al. Development of novel PROTAC Small-Molecule Degraders of MDM2 Protein and Peptidomimetic Inhibitors Targeting WDR5-MLL1 Protein-Protein Interaction.
- [4] Viktor Arnhold, et al. Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma. ncotarget. 2018 Jan 5; 9(2): 2304–2319.
