Arvinas Operations, Inc., 5 Science Park, 395 Winchester Avenue, New Haven, Connecticut 06511 United States.
J Med Chem. 2023 Jun 22;66(12):8281-8287. doi: 10.1021/acs.jmedchem.3c00740. Epub 2023 Jun 6.
Heterobifunctional PROTAC degraders are gaining attention as a differentiated therapeutic modality with the potential for oral dosing in the clinic. Belonging to the beyond Rule of Five domain of physicochemical property space, we have sought to understand the determinants of oral absorption for this class of molecules for the rapid development of novel oral agents. We have collected a large data set from PROTAC molecules that have been dosed orally and intravenously in rats to estimate the fraction absorbed from oral dosing. Through this estimation, effects from differential hepatic clearance are normalized, allowing for a better assessment of the absorption. We demonstrate that rats are less permissive to PROTAC absorption than mice. The physicochemical properties of the molecules are then evaluated once compounds are rank-ordered by the fraction absorbed. We derive suggested design constraints on physicochemical properties for PROTAC molecules that are associated with higher probability of being orally absorbed.
双功能 PROTAC 降解剂作为一种有区别的治疗模式引起了关注，具有在临床上口服给药的潜力。它们属于超出“五规则”的物理化学性质空间领域，我们一直致力于了解这一类分子口服吸收的决定因素，以便快速开发新型口服药物。我们从已在大鼠中进行过口服和静脉内给药的 PROTAC 分子中收集了大量数据集，以估算口服给药的吸收率。通过这种估算，可以将来自肝清除率差异的影响标准化，从而可以更好地评估吸收。我们证明大鼠比小鼠对 PROTAC 吸收的容忍度更低。然后，在根据吸收率对化合物进行排序后，对分子的物理化学性质进行评估。我们得出了与更高口服吸收率相关的 PROTAC 分子物理化学性质的建议设计约束。
