The New Frontier: Merging Molecular Glue Degrader and Antibody–Drug Conjugate Modalities To Overcome Strategic Challenges,Journal of Medicinal Chemistry

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The New Frontier: Merging Molecular Glue Degrader and Antibody–Drug Conjugate Modalities To Overcome Strategic Challenges
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-04 , DOI: 10.1021/acs.jmedchem.4c01289
Yam B Poudel ₁ , Ruchita R Thakore ₂ , Eugene P Chekler ₁

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Herein, we discuss advancements in the field of a unique class of antibody–drug conjugates (ADCs) named molecular glue–antibody conjugate (MAC). ADCs traditionally employ cytotoxic agents as payloads, and this approach has been used in all approved ADCs to treat cancer. Complementary to this approach, proteolysis targeting chimera (PROTAC) degrader antibody conjugates (DACs) provide a unique opportunity to deliver these bifunctional agents to tumors by using antibodies as a delivery mechanism to overcome the bioavailability issues encountered by PROTAC payloads. Recently, a cereblon binding monovalent degrader called molecular glues has been used in new ADCs that we have coined the term molecular–glue antibody conjugates (MACs). In this article, we intend to review advancements made in the field of targeted delivery of cereblon-based molecular glue degraders.

中文翻译：

新前沿：合并分子胶降解剂和抗体-药物偶联物模式以克服战略挑战

在本文中，我们讨论了一类独特的抗体-药物偶联物（ADC）领域的进展，称为分子胶-抗体偶联物（MAC）。ADC 传统上使用细胞毒性药物作为有效载荷，这种方法已用于所有批准的 ADC 来治疗癌症。作为对这种方法的补充，蛋白水解靶向嵌合体（PROTAC）降解剂抗体偶联物（DAC）提供了一个独特的机会，通过使用抗体作为递送机制来克服 PROTAC 有效载荷遇到的生物利用度问题，将这些双功能药物递送到肿瘤。最近，一种称为分子胶的脑结合单价降解剂已被用于新的 ADC，我们将其命名为分子胶抗体偶联物（MAC）。在本文中，我们打算回顾基于 Cereblon 的分子胶降解剂靶向递送领域取得的进展。

更新日期：2024-09-04

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