Milademetan

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C30H34Cl2FN5O4
Molecular Weight	618.526
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 5
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1(C)CCC2(CC1)N[C@H]([C@H](C3=C(F)C(Cl)=NC=C3)[C@]24C(=O)NC5=CC(Cl)=CC=C45)C(=O)N[C@@H]6CC[C@H](OC6)C(N)=O

InChI

InChIKey=RYAYYVTWKAOAJF-QISPRATLSA-N

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

HIDE SMILES / InChI

Molecular Formula	C30H34Cl2FN5O4
Molecular Weight	618.526
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	5 / 5
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://www.chemietek.com/ds-3032--milademetan---ds-3032b-details.aspx | https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=NCI_Thesaurus&code=C141432 | https://www.ncbi.nlm.nih.gov/pubmed/29490944

DS-3032 (Milademetan) is an orally available, potent and selective inhibitor of the p53-MDM2 (murine double minute 2) interaction. Milademetan binds to, and prevents the binding of MDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. Milademetan is 10-fold more potent than the first-generation inhibitor nutlin-3a. By preventing this MDM2-p53 interaction, the proteasome-mediated enzymatic degradation of p53 is inhibited and the transcriptional activity of p53 is restored. This results in the restoration of p53 signaling and leads to the p53-mediated induction of tumor cell apoptosis. DS-3032 is currently being evaluated in three phase 1 clinical trials for solid and hematological malignancies, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) in blast phase, lymphoma and myelodysplastic syndrome (MDS).

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
p53-binding protein Mdm-2 9 Target ID: CHEMBL5023 Sources: http://www.freepatentsonline.com/WO2017069289A1.pdf	Inhibitor 8504

C_max

Value	Dose	Analyte	Population
429 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
692 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1140 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	120 mg single, oral dose: 120 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
625 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	60 mg 1 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
995 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	90 mg 1 times / day multiple, oral dose: 90 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1230 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	120 mg 1 times / day multiple, oral dose: 120 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
718 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/34080309/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
675 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/34080309/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED

AUC

Value	Dose	Analyte	Population
6320 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
13400 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
25500 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	120 mg single, oral dose: 120 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
10300 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	60 mg 1 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
20300 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	90 mg 1 times / day multiple, oral dose: 90 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
25600 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	120 mg 1 times / day multiple, oral dose: 120 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
14698 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/34080309/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
13595 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/34080309/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED

T_1/2

Value	Dose	Analyte	Population
15.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
15.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
17.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	120 mg single, oral dose: 120 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
18.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	60 mg 1 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
20.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	90 mg 1 times / day multiple, oral dose: 90 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
26.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/33686772/	120 mg 1 times / day multiple, oral dose: 120 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MILADEMETAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
20.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/34080309/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
21.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/34080309/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	MILADEMETAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED

F_unbound

Value	Dose	Co-administered	Analyte	Population
20% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/34080309/	unknown		MILADEMETAN plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

PubMed

Title	Date	PubMed
The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy.	2018-11-05	30253242
Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition.	2018-05-15	29490944
Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma.	2018-01-05	29416773

Sample Use Guides

In Vivo Use Guide

4 days of daily treatment with gavages of 50 mg/kg followed by 2 days without treatment for 30 consecutive days.

Route of Administration: Oral

Substance Class	Chemical Created by `admin` on `Tue Apr 01 18:04:03 GMT 2025` Edited by `admin` on `Tue Apr 01 18:04:03 GMT 2025`
Record UNII	R3I80TLN7S
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

L-erythro-Hexonamide, 2,6-anhydro-5-[[[(3?R,4?S,5?R)-6??-chloro-4?-(2-chloro-3-fluoro-4-pyridinyl)-1??,2??-dihydro-4,4-dimethyl-2??-oxodispiro[cyclohexane-1,2?-pyrrolidine-3?,3??-[3H]indol]-5?-yl]carbonyl]amino]-3,4,5-trideoxy-

Preferred Name

English

Milademetan

Official Name

English

(3?R,4?S,5?R)-N-[(3R,6S)-6-carbamoyloxan-3-yl]-6??-chloro-4?-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2??-oxo-1??,2??-dihydrodispiro[cyclohexane-1,2?-pyrrolidine-3?,3??-indole]-5?-carboxamide

Systematic Name

English

MDM2 INHIBITOR DS-3032

Common Name

English

MILADEMETAN [USAN]

Common Name

English

DS-3032

Code

English

milademetan [INN]

Common Name

English

Milademetan [WHO-DD]

Common Name

English

2,6-ANHYDRO-5-((((3'R,4'S,5'R)-6''-CHLORO-4'-(2-CHLORO-3-FLUORO-4-PYRIDINYL)-1'',2''-DIHYDRO-4,4-DIMETHYL-2''-OXODISPIRO(CYCLOHEXANE-1,2'-PYRROLIDINE-3',3''-(3H)INDOL)-5'-YL)CARBONYL)AMINO)-3,4,5-TRIDEOXY-L-ERYTHRO-HEXONAMIDE

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C129839