| 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=CC(Cl)=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 |
MOL RATIO
1 MOL RATIO (average) |
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 4 / 4 |
| E/Z Centers | 0 |
| Optical Activity | UNSPECIFIED |
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
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Sourcing
PubMed
Patents
Sample Use Guides
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.
