Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.
C4 Therapeutics, 490 Arsenal Way, Suite 200, Watertown, MA 02472, USA.
Drug Discov Today. 2020 Jun;25(6):969-982. doi: 10.1016/j.drudis.2020.03.012. Epub 2020 Apr 13.
Targeted protein degraders are an emerging modality. Their properties fall outside the traditional small-molecule property space and are in the 'beyond rule of 5' space. Consequently, drug discovery programs focused on developing orally bioavailable degraders are expected to face complex drug metabolism and pharmacokinetics (DMPK) challenges compared with traditional small molecules. Nevertheless, little information is available on the DMPK optimization of oral degraders. Therefore, in this review, we discuss our experience of these DMPK optimization challenges and present methodologies and strategies to overcome the hurdles dealing with this new small-molecule modality, specifically in developing oral degraders to treat cancer.
靶向蛋白降解剂是一种新兴的治疗模式。其性质超出了传统小分子药物的性质范围，属于“超越 5 规则”的范畴。因此，与传统小分子药物相比，专注于开发口服生物可利用降解剂的药物发现计划预计将面临复杂的药物代谢和药代动力学（DMPK）挑战。然而，目前关于口服降解剂的 DMPK 优化的信息有限。因此，在这篇综述中，我们讨论了我们在这些 DMPK 优化挑战方面的经验，并介绍了克服这些新小分子治疗模式相关障碍的方法和策略，特别是在开发用于治疗癌症的口服降解剂方面。
