Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality with the potential to open target space not accessible to conventional small molecules via a degradation-based mechanism; however, their bifunctional nature can result in physicochemical properties that breach commonly accepted limits for small-molecule oral drugs. We offer a drug metabolism and pharmacokinetics (DMPK) perspective on the optimisation of oral PROTACs across a diverse set of projects within Oncology R&D at AstraZeneca, highlighting some of the challenges that they have presented to our established screening cascade. Furthermore, we challenge some of the perceptions and dogma surrounding the feasibility of oral PROTACS and demonstrate that acceptable oral PK properties for this modality can be regularly achievable despite the physicochemical property challenges they present.

蛋白水解靶向嵌合体 (PROTACs) 是一种新兴的治疗方式，具有通过基于降解的机制打开常规小分子无法进入的靶空间的潜力；然而，它们的双功能特性可能导致其物理化学性质超出小分子口服药物普遍接受的限制。我们提供了药物代谢和药代动力学 (DMPK) 的观点，以优化阿斯利康肿瘤学研发内的一系列不同项目中的口服 PROTAC，突出了它们对我们已建立的筛选级联提出的一些挑战。此外，