| RRC ID |
65140
|
| 著者 |
Ward GA, Lewis EJ, Ahn JS, Johnson CN, Lyons JF, Martins V, Munck JM, Rich SJ, Smyth T, Thompson NT, Williams PA, Wilsher NE, Wallis NG, Chessari G.
|
| タイトル |
ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth.
|
| ジャーナル |
Mol Cancer Ther
|
| Abstract |
Because of their roles in the evasion of apoptosis, inhibitor of apoptosis proteins (IAP) are considered attractive targets for anticancer therapy. Antagonists of these proteins have the potential to switch prosurvival signaling pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single-agent efficacy. ASTX660 is a potent, non-peptidomimetic antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells, and in vivo in xenograft models. The compound binds to the isolated BIR3 domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft tissue, direct antagonism of XIAP was demonstrated by measuring its displacement from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2, resulting in downstream effects of NIK stabilization and activation of noncanonical NF-κB signaling, demonstrated cIAP1/2 antagonism. Treatment with ASTX660 led to TNFα-dependent induction of apoptosis in various cancer cell lines in vitro, whereas dosing in mice bearing breast and melanoma tumor xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase I-II clinical trial (NCT02503423), and we propose that its antagonism of cIAP1/2 and XIAP may offer improved efficacy over first-generation antagonists that are more cIAP1/2 selective. Mol Cancer Ther; 17(7); 1381-91. ©2018 AACR.
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| 巻・号 |
17(7)
|
| ページ |
1381-1391
|
| 公開日 |
2018-7-1
|
| DOI |
10.1158/1535-7163.MCT-17-0848
|
| PII |
1535-7163.MCT-17-0848
|
| PMID |
29695633
|
| MeSH |
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Cell Line, Tumor
Cell Proliferation / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Humans
Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
Inhibitor of Apoptosis Proteins / chemistry
Inhibitor of Apoptosis Proteins / metabolism
Mice
Molecular Mimicry
Protein Interaction Domains and Motifs / drug effects
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / metabolism*
X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
X-Linked Inhibitor of Apoptosis Protein / chemistry
X-Linked Inhibitor of Apoptosis Protein / metabolism
Xenograft Model Antitumor Assays
|
| IF |
5.615
|
| リソース情報 |
| ヒト・動物細胞 |
MMAc·SF(RCB1200) |
