U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C28H35Cl2NO5S
Molecular Weight 568.552
Optical Activity UNSPECIFIED
Defined Stereocenters 4 / 4
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of NAVTEMADLIN

SMILES

CC(C)[C@@H](CS(=O)(=O)C(C)C)N1[C@@H]([C@H](C[C@](C)(CC(O)=O)C1=O)C2=CC(Cl)=CC=C2)C3=CC=C(Cl)C=C3

InChI

InChIKey=DRLCSJFKKILATL-YWCVFVGNSA-N
InChI=1S/C28H35Cl2NO5S/c1-17(2)24(16-37(35,36)18(3)4)31-26(19-9-11-21(29)12-10-19)23(20-7-6-8-22(30)13-20)14-28(5,27(31)34)15-25(32)33/h6-13,17-18,23-24,26H,14-16H2,1-5H3,(H,32,33)/t23-,24-,26-,28-/m1/s1

HIDE SMILES / InChI

Molecular Formula C28H35Cl2NO5S
Molecular Weight 568.552
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 4 / 4
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/25567130

p53 is a critical tumor suppressor and is the most frequently inactivated gene in human cancer. Inhibition of the interaction of p53 with its negative regulator MDM2 represents a promising clinical strategy to treat p53 wild-type tumors. AMG 232 is a potential best-in-class inhibitor of the MDM2-p53 interaction and is currently in clinical trials. Based on X-ray cocrystal structures a model of AMG 232 bound to MDM2 was developed. The model shows that the m-chlorophenyl, the p-chlorophenyl, and C-linked isopropyl fragments of AMG 232 bind to the Leu 26(p53), Trp 23(p53), and Phe 19(p53) pockets of MDM2, respectively. The carboxylic acid forms a salt bridge with His 96 and the isopropyl sulfone forms a novel interaction with the glycine shelf region of MDM2. AMG 232 in phase II in combination with trametinib and dabrafenib in subjects with metastatic melanoma; in phase I for the treatment of solid tumors, multiple myeloma and Acute Myeloid Leukemia.

Originator

Curator's Comment: Departments of Therapeutic Discovery, Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
0.6 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Doses

Doses

DosePopulationAdverse events​
480 mg 1 times / day multiple, oral
Highest studied dose
Dose: 480 mg, 1 times / day
Route: oral
Route: multiple
Dose: 480 mg, 1 times / day
Sources: Page: p.834
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources: Page: p.834
DLT: Neutropenia...
Dose limiting toxicities:
Neutropenia (grade 3, 16.7%)
Sources: Page: p.834
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
Disc. AE: Malaise, Thrombocytopenia...
AEs leading to
discontinuation/dose reduction:
Malaise (1.5%)
Thrombocytopenia (1.5%)
Neutropenia (1.5%)
Intestinal adhesion lysis (1.5%)
Vomiting (5.9%)
Oculogyric crisis (1.5%)
Fatigue (2.9%)
ECOG performance status worsened (1.5%)
Nausea (1.5%)
Dyspnea (1.5%)
Pulmonary embolism and thrombosis (1.5%)
Asthenia (1.5%)
Sources: Page: p.834, 835
360 mg 1 times / day multiple, oral
Studied dose
Dose: 360 mg, 1 times / day
Route: oral
Route: multiple
Dose: 360 mg, 1 times / day
Sources: Page: p.834
unhealthy, ADULT
n = 4
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 4
Sources: Page: p.834
DLT: Thrombocytopenia...
Dose limiting toxicities:
Thrombocytopenia (grade 4, 25%)
Sources: Page: p.834
AEs

AEs

AESignificanceDosePopulation
Neutropenia grade 3, 16.7%
DLT, Disc. AE
480 mg 1 times / day multiple, oral
Highest studied dose
Dose: 480 mg, 1 times / day
Route: oral
Route: multiple
Dose: 480 mg, 1 times / day
Sources: Page: p.834
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources: Page: p.834
Asthenia 1.5%
Disc. AE
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
Dyspnea 1.5%
Disc. AE
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
ECOG performance status worsened 1.5%
Disc. AE
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
Intestinal adhesion lysis 1.5%
Disc. AE
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
Malaise 1.5%
Disc. AE
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
Nausea 1.5%
Disc. AE
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
Neutropenia 1.5%
Disc. AE
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
Oculogyric crisis 1.5%
Disc. AE
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
Pulmonary embolism and thrombosis 1.5%
Disc. AE
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
Thrombocytopenia 1.5%
Disc. AE
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
Fatigue 2.9%
Disc. AE
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
Vomiting 5.9%
Disc. AE
240 mg 1 times / day multiple, oral
Studied dose
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.834, 835
unhealthy, ADULT
n = 68
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 68
Sources: Page: p.834, 835
Thrombocytopenia grade 4, 25%
DLT
360 mg 1 times / day multiple, oral
Studied dose
Dose: 360 mg, 1 times / day
Route: oral
Route: multiple
Dose: 360 mg, 1 times / day
Sources: Page: p.834
unhealthy, ADULT
n = 4
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 4
Sources: Page: p.834
PubMed

PubMed

TitleDatePubMed
The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents.
2015 Mar
Patents

Patents

Sample Use Guides

Given as an oral tablet in escalating doses
Route of Administration: Oral
Activation of p53 signaling was determined by measuring induction of p21 mRNA, a direct transcriptional target of p53, in three p53 wild-type tumor cell lines (SJSA-1, HCT116, and ACHN). AMG 232 treatment (0.1, 1, or 10 μmol/L) caused robust p21 mRNA induction between 9.76- and 34.9-fold with IC50 values ranging from 12.8 to 46.8 nmol/L. Similarly, cell proliferation assays demonstrated that AMG 232 treatment potently inhibited proliferation of these tumor cell lines with IC50 values ranging from 9.4 to 23.8 nmol/L. In the 23 p53 wild-type cell lines we evaluated, AMG 232 treatment inhibited the growth of cells with IC50 values ranging from 0.1 to 1 μmol/L. As expected, there was no significant effect on growth of the p53-mutant lines.
Substance Class Chemical
Created
by admin
on Sat Dec 16 08:01:54 GMT 2023
Edited
by admin
on Sat Dec 16 08:01:54 GMT 2023
Record UNII
7R7G6EH5UL
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
NAVTEMADLIN
USAN   INN  
Official Name English
MDM2 INHIBITOR AMG-232
Common Name English
3-Piperidineacetic acid, 5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(1S)-2-methyl-1-[[(1-methylethyl)sulfonyl]methyl]propyl]-2-oxo-, (3R,5R,6S)-
Systematic Name English
AMG 232 [WHO-DD]
Common Name English
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
Systematic Name English
NAVTEMADLIN [USAN]
Common Name English
navtemadlin [INN]
Common Name English
{(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3- methyl-1-[(2S)-3-methyl-1-(propane-2-sulfonyl)butan2-yl]-2-oxopiperidin-3-yl}acetic acid
Systematic Name English
AMG-232
Code English
KRT-232
Code English
Classification Tree Code System Code
FDA ORPHAN DRUG 735120
Created by admin on Sat Dec 16 08:01:54 GMT 2023 , Edited by admin on Sat Dec 16 08:01:54 GMT 2023
FDA ORPHAN DRUG 737220
Created by admin on Sat Dec 16 08:01:54 GMT 2023 , Edited by admin on Sat Dec 16 08:01:54 GMT 2023
NCI_THESAURUS C129839
Created by admin on Sat Dec 16 08:01:54 GMT 2023 , Edited by admin on Sat Dec 16 08:01:54 GMT 2023
Code System Code Type Description
USAN
KL-35
Created by admin on Sat Dec 16 08:01:54 GMT 2023 , Edited by admin on Sat Dec 16 08:01:54 GMT 2023
PRIMARY
PUBCHEM
58573469
Created by admin on Sat Dec 16 08:01:54 GMT 2023 , Edited by admin on Sat Dec 16 08:01:54 GMT 2023
PRIMARY
INN
11546
Created by admin on Sat Dec 16 08:01:54 GMT 2023 , Edited by admin on Sat Dec 16 08:01:54 GMT 2023
PRIMARY INN
NCI_THESAURUS
C116624
Created by admin on Sat Dec 16 08:01:54 GMT 2023 , Edited by admin on Sat Dec 16 08:01:54 GMT 2023
PRIMARY
EPA CompTox
DTXSID101025652
Created by admin on Sat Dec 16 08:01:54 GMT 2023 , Edited by admin on Sat Dec 16 08:01:54 GMT 2023
PRIMARY
FDA UNII
7R7G6EH5UL
Created by admin on Sat Dec 16 08:01:54 GMT 2023 , Edited by admin on Sat Dec 16 08:01:54 GMT 2023
PRIMARY
DRUG BANK
DB15299
Created by admin on Sat Dec 16 08:01:54 GMT 2023 , Edited by admin on Sat Dec 16 08:01:54 GMT 2023
PRIMARY
CAS
1352066-68-2
Created by admin on Sat Dec 16 08:01:54 GMT 2023 , Edited by admin on Sat Dec 16 08:01:54 GMT 2023
PRIMARY
SMS_ID
100000184093
Created by admin on Sat Dec 16 08:01:54 GMT 2023 , Edited by admin on Sat Dec 16 08:01:54 GMT 2023
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
Kd
TARGET -> INHIBITOR
Related Record Type Details
ACTIVE MOIETY