组织蛋白酶-B可裂解连接子的快速，高产固相合成，用于靶向癌症治疗。,Bioconjugate Chemistry

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组织蛋白酶-B可裂解连接子的快速，高产固相合成，用于靶向癌症治疗。
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-12-04 , DOI: 10.1021/acs.bioconjchem.0c00563
Alla Pryyma ₁ , Shanal Gunasekera ₁ , Joshua Lewin ₁ , David M Perrin ₁

Affiliation

抗体-药物偶联物（ADC）构成了新兴的一类抗癌药物，可选择性地向肿瘤提供有效的有效载荷，同时避免了与常规化学疗法相关的全身毒性。ADC开发的关键是血清稳定的连接子，该连接子旨在在靶细胞内部分解，从而释放出有毒的有效载荷。包含缬氨酸-瓜氨酸（Val-Cit）基序的蛋白酶可裂解的连接子已成功整合到三个FDA批准的ADC中，并在许多临床前候选物中被发现。在本文中，我们提出了一种高产且简便的Val-Cit接头合成策略，该策略避免了广泛的保护基操纵和与先前合成相关的费力色谱，并且提供的收率比标准方法高10倍。该方法易于扩展，并利用了经济高效的偶联剂和高负荷的2-氯三苯甲基氯（2-CTC）树脂。模块化允许在合成的最后阶段引入各种共轭手柄。方便地获得此类类似物有助于扩大可用的可酶裂解的连接子，以产生ADC。这种方法可以生成健壮且便捷的文库，并可以进一步探索包含非天然氨基酸作为选择性调节工具的接头类似物。方便地获得此类类似物有助于扩大可用的可酶裂解的连接子，以产生ADC。这种方法可以生成健壮且便捷的文库，并可以进一步探索包含非天然氨基酸作为选择性调节工具的接头类似物。方便地获得此类类似物有助于扩大可用的可酶裂解的连接子，以产生ADC。这种方法可以生成健壮且便捷的文库，并可以进一步探索包含非天然氨基酸作为选择性调节工具的接头类似物。

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Rapid, High-Yielding Solid-Phase Synthesis of Cathepsin-B Cleavable Linkers for Targeted Cancer Therapeutics

Antibody–drug conjugates (ADCs) constitute an emerging class of anticancer agents that deliver potent payloads selectively to tumors while avoiding systemic toxicity associated with conventional chemotherapeutics. Critical to ADC development is a serum-stable linker designed to decompose inside targeted cells thereby releasing the toxic payload. A protease-cleavable linker comprising a valine-citrulline (Val-Cit) motif has been successfully incorporated into three FDA-approved ADCs and is found in numerous preclinical candidates. Herein, we present a high-yielding and facile synthetic strategy for a Val-Cit linker that avoids extensive protecting group manipulation and laborious chromatography associated with previous syntheses and provides yields that are up to 10-fold higher than by standard methods. This method is easily scalable and takes advantage of cost-effective coupling reagents and high loading 2-chlorotrityl chloride (2-CTC) resin. Modularity allows for introduction of various conjugation handles in final stages of the synthesis. Facile access to such analogues serves to expand the repertoire of available enzymatically cleavable linkers for ADC generation. This methodology empowers a robust and facile library generation and future exploration into linker analogues containing unnatural amino acids as a selectivity tuning tool.

更新日期：2020-12-16

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