Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release.
Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release.
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DOI：
10.1021/acs.jmedchem.3c00845
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发表时间：
2023-09-14
影响因子：
7.3
通讯作者：
Waring, Michael J.
中科院分区：
文献类型：
--
作者：
Morese, Pasquale A.;Anthony, Nahoum;Bodnarchuk, Michael;Jennings, Claire;Martin, Mathew P.;Noble, Richard A.;Phillips, Nicole;Thomas, Huw D.;Wang, Lan Z.;Lister, Andrew;Noble, Martin E. M.;Ward, Richard A.;Wedge, Stephen R.;Stewart, Hannah L.;Waring, Michael J.
细胞毒性化疗的一个主要缺点是缺乏对非癌细胞的选择性。将细胞毒性药物靶向递送至肿瘤细胞是癌症研究中的长期目标。我们提出，共价抑制剂可以通过共价结合促进的加成-消除机制，与迈克尔受体的β-位缀合，以递送细胞毒性剂。对模型系统的研究表明，结合的5-氟尿嘧啶（5 FU）可以释放后，巯基添加在相关的时间尺度。合成了一系列共价结合的表皮生长因子受体（EGFR）抑制剂5-FU衍生物。实现所需的5 FU释放被证明取决于化合物的电子学和几何形状。质谱和NMR研究证明苯胺基喹唑啉丙烯酸酯缀合物结合EGFR，释放5 FU。这项工作确立了丙烯酸酯可用于在与蛋白质共价结合后释放缀合分子，并可用于开发靶向治疗剂。
A major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the β-position of the Michael acceptor, via an addition–elimination mechanism promoted by covalent binding. Studies on model systems showed that conjugated 5-fluorouracil (5FU) could be released upon thiol addition in relevant time scales. A series of covalent epidermal growth factor receptor (EGFR) inhibitors were synthesized as their 5FU derivatives. Achieving the desired release of 5FU was demonstrated to depend on the electronics and geometry of the compounds. Mass spectrometry and NMR studies demonstrated an anilinoquinazoline acrylate ester conjugate bound to EGFR with the release of 5FU. This work establishes that acrylates can be used to release conjugated molecules upon covalent binding to proteins and could be used to develop targeted therapeutics.
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影响因子：
1.2
作者：
Cazzamalli S;Corso AD;Neri D
通讯作者：
Neri D
影响因子：
7.3
作者：
Finlay, M. Raymond V.;Anderton, Mark;Wrigley, Gail L.
通讯作者：
Wrigley, Gail L.
影响因子：
7.3
作者：
Ward, Richard A.;Anderton, Mark J.;Waring, Michael J.
通讯作者：
Waring, Michael J.
影响因子：
2.7
作者：
Zhou, Wenjun;Ercan, Dalia;Jaenne, Pasi A.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
11.2
作者：
Engelman, Jeffrey A.;Zejnullahu, Kreshnik;Janne, Pasi A.
通讯作者：
Janne, Pasi A.