School of Chemical Sciences, The University of Auckland, 23 Symonds St., Auckland 1010, New Zealand.
Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand.
Bioconjug Chem. 2024 Jul 17;35(7):1007-1014. doi: 10.1021/acs.bioconjchem.4c00199. Epub 2024 Jun 14.
The synthesis of linker-payloads is a critical step in developing antibody-drug conjugates (ADCs), a rapidly advancing therapeutic approach in oncology. The conventional method for synthesizing cathepsin B-labile dipeptide linkers, which are commonly used in ADC development, involves the solution-phase assembly of cathepsin B-sensitive dipeptides, followed by the installation of self-immolative -aminobenzyl carbonate to facilitate the attachment of potent cytotoxic payloads. However, this approach is often low yield and laborious, especially when extending the peptide chain with components like glutamic acid to improve mouse serum stability or charged amino acids or poly(ethylene glycol) moieties to enhance linker hydrophilicity. Here, we introduce a novel approach utilizing late-stage desulfurization chemistry, enabling safe, facile, and cost-effective access to the cathepsin B-cleavable linker, Val-Ala-PABC-MMAE, on resin for the first time.
Linker-payloads 的合成是开发抗体药物偶联物（ADC）的关键步骤，ADC 是肿瘤学领域中一种快速发展的治疗方法。在 ADC 开发中常用的组织蛋白酶 B 不稳定二肽接头的传统合成方法涉及组织蛋白酶 B 敏感二肽的溶液相组装，然后安装自毁性 - 氨基苄基碳酸酯，以方便有效细胞毒性有效载荷的连接。然而，这种方法通常产量低且费力，尤其是在通过谷氨酸等成分扩展肽链以提高小鼠血清稳定性或带电荷的氨基酸或聚（乙二醇）部分以增强接头亲水性时。在这里，我们介绍了一种利用后期脱硫化学的新方法，首次在树脂上实现了安全、简便且具有成本效益的方法，以获得可切割组织蛋白酶 B 的接头 Val-Ala-PABC-MMAE。
