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
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
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 |
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/24456472Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/25567130
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24456472
Curator's Comment: Departments of Therapeutic Discovery, Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc.
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1907611 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25567130 |
0.6 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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: 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%) Sources: Page: p.834, 835Thrombocytopenia (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%) |
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
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: 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
Title | Date | PubMed |
---|---|---|
Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. | 2014 Aug 14 |
|
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 |
|
Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and monkeys: in vitro-in vivo correlation. | 2015 |
|
The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents. | 2015 Mar |
Patents
Sample Use Guides
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/25567130
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
Edited
Sat Dec 16 08:01:54 GMT 2023
by
admin
on
Sat Dec 16 08:01:54 GMT 2023
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Record UNII |
7R7G6EH5UL
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Record Status |
Validated (UNII)
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Record Version |
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-
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Classification Tree | Code System | Code | ||
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FDA ORPHAN DRUG |
735120
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FDA ORPHAN DRUG |
737220
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NCI_THESAURUS |
C129839
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KL-35
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58573469
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11546
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C116624
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DTXSID101025652
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7R7G6EH5UL
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DB15299
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100000184093
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