MILADEMETAN TOSYLATE MONOHYDRATE

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C30H34Cl2FN5O4.C7H8O3S.H2O
Molecular Weight	808.743
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 5
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of MILADEMETAN TOSYLATE MONOHYDRATE

SMILES

O.CC1=CC=C(C=C1)S(O)(=O)=O.CC2(C)CCC3(CC2)N[C@H]([C@H](C4=C(F)C(Cl)=NC=C4)[C@]35C(=O)NC6=CC(Cl)=CC=C56)C(=O)N[C@@H]7CC[C@H](OC7)C(N)=O

InChI

InChIKey=WPJOGWGXMTUHPW-CIPNXXNHSA-N

InChI=1S/C30H34Cl2FN5O4.C7H8O3S.H2O/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;1-6-2-4-7(5-3-6)11(8,9)10;/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);2-5H,1H3,(H,8,9,10);1H2/t16-,20+,21+,23-,30-;;/m1../s1

HIDE SMILES / InChI

Description

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

Targets

Primary Target	Pharmacology	Condition	Potency
p53-binding protein Mdm-2 9	Inhibitor 8,504

C_max

Value	Dose	Analyte	Population
429 ng/mL	60 mg single, oral	MILADEMETAN plasma	Homo sapiens
692 ng/mL	90 mg single, oral	MILADEMETAN plasma	Homo sapiens
1140 ng/mL	120 mg single, oral	MILADEMETAN plasma	Homo sapiens
625 ng/mL	60 mg 1 times / day multiple, oral	MILADEMETAN plasma	Homo sapiens
995 ng/mL	90 mg 1 times / day multiple, oral	MILADEMETAN plasma	Homo sapiens
1230 ng/mL	120 mg 1 times / day multiple, oral	MILADEMETAN plasma	Homo sapiens
718 ng/mL	100 mg single, oral	MILADEMETAN plasma	Homo sapiens
675 ng/mL	100 mg single, oral	MILADEMETAN plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
6320 ng × h/mL	60 mg single, oral	MILADEMETAN plasma	Homo sapiens
13400 ng × h/mL	90 mg single, oral	MILADEMETAN plasma	Homo sapiens
25500 ng × h/mL	120 mg single, oral	MILADEMETAN plasma	Homo sapiens
10300 ng × h/mL	60 mg 1 times / day multiple, oral	MILADEMETAN plasma	Homo sapiens
20300 ng × h/mL	90 mg 1 times / day multiple, oral	MILADEMETAN plasma	Homo sapiens
25600 ng × h/mL	120 mg 1 times / day multiple, oral	MILADEMETAN plasma	Homo sapiens
14698 ng × h/mL	100 mg single, oral	MILADEMETAN plasma	Homo sapiens
13595 ng × h/mL	100 mg single, oral	MILADEMETAN plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
15.1 h	60 mg single, oral	MILADEMETAN plasma	Homo sapiens
15.4 h	90 mg single, oral	MILADEMETAN plasma	Homo sapiens
17.9 h	120 mg single, oral	MILADEMETAN plasma	Homo sapiens
18.1 h	60 mg 1 times / day multiple, oral	MILADEMETAN plasma	Homo sapiens
20.9 h	90 mg 1 times / day multiple, oral	MILADEMETAN plasma	Homo sapiens
26.1 h	120 mg 1 times / day multiple, oral	MILADEMETAN plasma	Homo sapiens
20.7 h	100 mg single, oral	MILADEMETAN plasma	Homo sapiens
21.3 h	100 mg single, oral	MILADEMETAN plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
20%	unknown		MILADEMETAN plasma	Homo sapiens

PubMed

PubMed

Show entries

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

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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

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Name

Type

Language

DS-3032 TOSYLATE MONOHYDRATE

Preferred Name

English

MILADEMETAN TOSYLATE MONOHYDRATE

Common Name

English

(3'R,4'S,5'R)-N-((3R,6S)-6-CARBAMOYLTETRAHYDRO-2H-PYRAN-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 MONO(4-METHYLBENZENESULFONATE) MONOHYDRATE

Systematic Name

English

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