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. 2023 Jun 22;66(12):8281-8287.
doi: 10.1021/acs.jmedchem.3c00740. Epub 2023 Jun 6.

Physicochemical Property Determinants of Oral Absorption for PROTAC Protein Degraders

Keith R Hornberger  1 , Erika M V Araujo  1
Affiliations

Physicochemical Property Determinants of Oral Absorption for PROTAC Protein Degraders

Keith R Hornberger et al. J Med Chem. .

Abstract

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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Conflict of interest statement

The authors declare the following competing financial interest(s): Research was conducted at Arvinas Operations, Inc. where the authors are employees and shareholders.

Figures

Scheme 1
Scheme 1. Structures of a PROTAC and Induced Trimer Complex between Target Protein:PROTAC:E3 Ligase
Figure 1
Figure 1
Comparison of the fractions absorbed of PROTAC molecules in rats and mice using the fa × fg term.
Figure 2
Figure 2
Estimated fraction absorbed in rats as a function of the physicochemical properties of the PROTAC molecules in the Arvinas database. The x-axis of discrete variables has been jittered for clarity.
Figure 3
Figure 3
Estimated fraction absorbed in rats as a function of AB-MPS score of the PROTAC molecules in the Arvinas database.
Figure 4
Figure 4
Representative ULMs used in physicochemical property budget analysis.
Figure 5
Figure 5
Analysis of the physicochemical property budget with respect to the design of orally bioavailable PROTACs based on targeting (A) VHL or (B) CRBN as E3 with representative ULMs depicted in Figure 4.
See this image and copyright information in PMC

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