| RRC ID |
78157
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| 著者 |
Gunasekaran P, Hwang YS, Lee GH, Park J, Kim JG, La YK, Park NY, Kothandaraman R, Yim MS, Choi J, Kim HN, Park IY, Lee SJ, Kim MH, Cha-Molstad H, Shin SY, Ryu EK, Bang JK.
|
| タイトル |
Degradation of Polo-like Kinase 1 by the Novel Poly-Arginine N-Degron Pathway PROTAC Regulates Tumor Growth in Nonsmall Cell Lung Cancer.
|
| ジャーナル |
J Med Chem
|
| Abstract |
Polo-like kinase 1 (PLK1), which is crucial in cell cycle regulation, is considered a promising anticancer drug target. Herein, we present the N-degron pathway-based proteolysis targeting chimera (PROTAC) for PLK1 degradation, targeting the Polo-box domain (PBD). We identified DD-2 as the most potent PROTAC that selectively induces PLK1 degradation in cancer cells, including HeLa and nonsmall cell lung cancer (NSCLC), through the N-degron pathway. DD-2 exhibited significant in vitro anticancer effects, inducing G2/M arrest and apoptosis in HeLa and NSCLC cell lines. DD-2 showed significant tumor growth inhibition in a xenograft mouse model using HeLa and NSCLC cell lines, highlighting its potential in cancer treatment. Furthermore, the combination of DD-2 with tyrosine kinase inhibitor (TKI), osimertinib, effectively suppressed tumor growth in double-mutated H1975 cell lines, emphasizing DD-2's potential in combination cancer therapies. Collectively, this study demonstrates the potential of the N-degron pathway, especially using DD-2, for targeted cancer therapies.
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| 公開日 |
2023-12-17
|
| DOI |
10.1021/acs.jmedchem.3c01493
|
| PMID |
38105611
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| リソース情報 |
| ヒト・動物細胞 |
HeLa
A549(RCB0098)
PC9(RCB4455) |
