NAVTEMADLIN

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 Search

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

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24456472
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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Tumour suppressor p53/oncoprotein Mdm2 6 Target ID: CHEMBL1907611 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25567130	Inhibitor 8297		0.6 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Melanoma 88 Sources: https://clinicaltrials.gov/ct2/show/NCT02110355	Primary	Phase II 1132	Unknown Approved Use Unknown
Acute myeloid leukemia 136 Sources: https://clinicaltrials.gov/ct2/show/NCT02016729	Primary	Phase I 428	Unknown Approved Use Unknown
Multiple myeloma 159 Sources: https://clinicaltrials.gov/ct2/show/NCT01723020	Primary	Phase I 428	Unknown Approved Use Unknown
Glioblastoma 65 Sources: https://clinicaltrials.gov/ct2/show/NCT01723020	Primary	Phase I 428	Unknown Approved Use Unknown

Doses

Dose	Population	Adverse 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 Page: p.834	DLT: Neutropenia... Dose limiting toxicities: Neutropenia (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 Page: p.834	DLT: Thrombocytopenia... Dose limiting toxicities: Thrombocytopenia (grade 4, 25%) Sources: https://pubmed.ncbi.nlm.nih.gov/31359240 Page: p.834

AEs

AE	Significance	Dose	Population
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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 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: https://pubmed.ncbi.nlm.nih.gov/31359240 Page: p.834

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P009CPN	https://www.1pchem.com/search?query=1P009CPN
AK Scientific	V2654	https://aksci.com/item_detail.php?cat=V2654
AOBIOUS INC	AOB87308	http://aobious.com/aobious/search?search_query=AOB87308
ApexBio Technology	A8804	https://www.apexbt.com/catalogsearch/result/?q=A8804
AstaTech	C14630	http://astatechinc.com/CPSResult.php?CRNO=C14630
Axon MedChem	2639	https://www.axonmedchem.com/product/2639
BLD Pharm	BD630168	http://www.bldpharm.com/search/Search.html?keyword=BD630168
Chem Scene	CS-3282	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-3282
KeyOrganics	AS-17007	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-17007
MedChem Express	HY-12296	https://www.medchemexpress.com/search.html?q=HY-12296&ft=&fa=&fp=
MolPort	MolPort-039-142-126	https://www.molport.com/shop/molecule-link/MolPort-039-142-126
Molnova	M11426	https://www.molnova.com/en/serch-list.html?keywords=M11426
eMolecules	50283277	https://orderbb.emolecules.com/search/#?query=50283277
mcule	MCULE-4669382955	https://mcule.com/MCULE-4669382955/
mcule	MCULE-7084057598	https://mcule.com/MCULE-7084057598/

PubMed

Title	Date	PubMed
Optimization beyond AMG 232: discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction.	2014 Aug 15	25042256

Patents

Sample Use Guides

In Vivo Use Guide

Given as an oral tablet in escalating doses

Route of Administration: Oral

In Vitro Use Guide

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.

Name

Type

Language

NAVTEMADLIN

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