| Item type |
学術雑誌論文 / Journal Article(1) |
| 公開日 |
2022-01-27 |
| タイトル |
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タイトル |
A radiobrominated tyrosine kinase inhibitor for egfr with l858r/t790m mutations in lung carcinoma |
| 言語 |
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言語 |
eng |
| 資源タイプ |
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資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
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資源タイプ |
journal article |
| ID登録 |
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ID登録 |
10.24517/00065235 |
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ID登録タイプ |
JaLC |
| 著者 |
Fawwaz, Muammar
Mishiro, Kenji
Nishii, Ryuichi
Makino, Akira
Kiyono, Yasushi
Shiba, Kazuhiro
Kinuya, Seigo
Ogawa, Kazuma
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| 著者別表示 |
三代, 憲司
柴, 和弘
絹谷, 清剛
小川, 数馬
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| 提供者所属 |
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内容記述タイプ |
Other |
|
内容記述 |
金沢大学疾患モデル総合研究センター |
| 書誌情報 |
Pharmaceuticals
巻 14,
号 3,
p. 256,
発行日 2021
|
| ISSN |
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収録物識別子タイプ |
ISSN |
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収録物識別子 |
1424-8247 |
| DOI |
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関連タイプ |
isIdenticalTo |
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識別子タイプ |
DOI |
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関連識別子 |
10.3390/ph14030256 |
| 出版者 |
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出版者 |
MDPI AG |
| 抄録 |
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内容記述タイプ |
Abstract |
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内容記述 |
Activating double mutations L858R/T790M in the epidermal growth factor receptor (EGFR) region are often observed as the cause of resistance to tyrosine kinase inhibitors (TKIs). Third‐generation EGFR‐TKIs, such as osimertinib and rociletinib (CO‐1686), was developed to target such resistance mutations. The detection of activating L858R/T790M mutations is necessary to select sensitive patients for therapy. Hence, we aimed to develop novel radiobromine‐labeled CO‐ 1686 as a positron emission tomography (PET) imaging probe for detecting EGFR L858R/T790M mutations. Nonradioactive brominated‐CO1686 (BrCO1686) was synthesized by the condensation of N‐(3‐[{2‐chloro‐5‐(trifluoromethyl)pyrimidin‐4‐yl}amino]‐5‐bromophenyl) acrylamide with the corresponding substituted 1‐(4‐[4‐amino‐3‐methoxyphenyl]piperazine‐1‐yl)ethan‐1‐one. The radi-obrominated [77 Br]BrCO1686 was prepared through bromodestannylation of the corresponding tributylstannylated precursor with [77Br]bromide and N‐chlorosuccinimide. Although we aimed to provide a novel PET imaging probe,77Br was used as an alternative radionuclide for76Br. We fun-damentally evaluated the potency of [77Br]BrCO1686 as a molecular probe for detecting EGFR L858R/T790M using human non‐small‐cell lung cancer (NSCLC) cell lines: H1975 (EGFR L858R/T790M), H3255 (EGFR L858R), and H441 (wild‐type EGFR). The BrCO1686 showed high cy-totoxicity toward H1975 (IC50 0.18 ± 0.06 μM) comparable to that of CO‐1686 (IC50 0.14 ± 0.05 μM). In cell uptake experiments, the level of accumulation of [77Br]BrCO1686 in H1975 was significantly higher than those in H3255 and H441 upon 4 h of incubation. The radioactivity of [77Br]BrCO1686 (136.3% dose/mg protein) was significantly reduced to 56.9% dose/mg protein by the pretreatment with an excess CO‐1686. These results indicate that the binding site of the radiotracers should be identical to that of CO‐1686. The in vivo accumulation of radioactivity of [77Br]BrCO1686 in H1975 tumor (4.51 ± 0.17) was higher than that in H441 tumor (3.71 ± 0.13) 1 h postinjection. Our results suggested that [77Br]BrCO1686 has specificity toward NSCLC cells with double mutations EGFR L858R/T790M compared to those in EGFR L858R and wild‐type EGFR. However, the in vivo accumulation of radioactivity in the targeted tumor needs to be optimized by structural modification. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. |
| 内容記述 |
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内容記述タイプ |
Other |
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内容記述 |
CC-BY 4.0 |
| 権利 |
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権利情報 |
Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). |
| 著者版フラグ |
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出版タイプ |
VoR |
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出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| 関連URI |
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識別子タイプ |
URI |
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関連識別子 |
http://www.mdpi.com/journal/pharmaceuticals |
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関連名称 |
http://www.mdpi.com/journal/pharmaceuticals |
ME-PR-SHIBA-K-14-256.pdf (747.1 kB)
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