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.
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