Milademetan

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=C4C=CC(Cl)=C5)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

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 8297

PubMed

Title	Date	PubMed
Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma.	2018 Jan 5	29416773
Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition.	2018 May 15	29490944
The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy.	2018 Nov 5	30253242

Patents

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

Name

Type

Language

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

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-tr

Systematic 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