Balanced Permeability Index is a Strong Predictor of Intestinal Absorption and Oral Bioavailability for Heterobifunctional Ligand-Directed Degraders

Ligand-directed degraders (LDDs) are heterobifunctional molecules that degrade proteins by engaging the ubiquitin-protein ligase (E3) system. LDDs consist of a target-engaging moiety, an E3 ligase-binding moiety and a bridging linker. Due to their size and physicochemical complexity these molecules do not adhere to well-established rules of lead optimization. The optimization of passive permeability remains a key challenge to develop orally bioavailable LDDs. To overcome this challenge, in this study we demonstrate that the Balanced Permeability Index (BPI)--a new metric that combines size, polarity and lipophilicity--is highly predictive of oral bioavailability for LDDs. Here, we introduce an additional parameter--called smallest maximum intramo-lecular distance (SMID)--to the original BPI index to account for cross sectional area of LDDs, termed BPILDD. With this new parameter, BPILDD can differentiate oral bioavailability of LDDs in our dataset more effectively than polarity, lipophilicity, or size separately. In addition, BPILDD is also more effective at identifying orally bioavailable LDDs than some in vitro measurements of cell permeability that traditionally inform bioavailability. This finding opens the possibility of employing BPILDD for the design and optimization of orally bioavailable LDDs to improve their drug metabolism and pharmacokinetics properties.