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.

No abstract

The ability to control the intracellular concentrations of proteins with small molecules has obvious implications for the treatment of cancer whose growth and spread is typically due to the dysregulation of just a small number of proteins. The ubiquitin proteasome system (UPS) is the tightly regulated machinery used by the cell to dispose of undesired proteins. We review herein how various components of the UPS can be targeted by small‐molecule intervention to realize global or even specific control of protein levels. Building on the success that inhibitors of the proteasome have had in the clinic over the past decade, a growing number of clinical candidates directed at the UPS are currently being evaluated as cancer therapies.