Designing Soluble PROTACs: Strategies and Preliminary Guidelines

Abstract

Solubility optimization is a crucial step to obtaining oral PROTACs. Here we measured the thermodynamic solubilities (log S) of 21 commercial PROTACs. Next, we measured BRlogD and log k w IAM (lipophilicity), EPSA, and Δ log k w IAM (polarity) and showed that lipophilicity plays a major role in governing log S, but a contribution of polarity cannot be neglected. Two-/three-dimensional descriptors calculated on conformers arising from conformational sampling and steered molecular dynamics failed in modeling solubility. Infographic tools were used to identify a privileged region of soluble PROTACs in a chemical space defined by BRlogD, log k w IAM and topological polar surface area, while machine learning provided a log S classification model. Finally, for three pairs of PROTACs we measured the solubility, lipophilicity, and polarity of the building blocks and identified the limits of estimating PROTAC solubility from the synthetic components. Overall, this paper provides promising guidelines for optimizing PROTAC solubility in early drug discovery programs.

Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton’s Tyrosine Kinase for the Treatment of Lymphoma

“…The absorption and metabolism of PROTACs involve complex biological processes, which are greatly influenced by physicochemical parameters including lipophilicity and solubility. However, these parameters were less disclosed in published reports and hard to be predicted or tested. ,, Considering that physicochemical parameters are closely related to molecular structures, we intended to focus on comparing the structural feature differences of PROTACs and orally bioavailable small-molecule drugs using dimensionality reduction analysis and model molecule validation, thereby providing structural clues for the rational design of orally bioavailable BTK-PROTACs. Our efforts identified a highly efficient and selective BTK-PROTAC C13 with excellent PK properties and pharmacodynamic (PD) efficacies.…”

Refinement of Computational Access to Molecular Physicochemical Properties: From Ro5 to bRo5

“…bRo5 compounds are often affected by solubility/permeability and thus intestinal absorption and oral bioavailability issues. 7 , 8 Therefore, to obtain new oral drugs in this space, molecular properties should be optimized in early drug discovery. 9 , 10 Because property-based drug discovery can be applied at different development stages, both computed and experimental descriptors are required.…”

“… 12 BRlogD works efficiently in the bRo5 chemical space, and it is crucial for the classification of PROTAC solubility. 7 ElogD is another chromatographic log D octanol/water surrogate developed internally by Pfizer. 13 Additionally, log k W IAM implements an immobilized artificial membrane (IAM) column, which provides a lipophilicity index in an environment resembling the membrane phospholipids.…”

“…bRo5 compounds are often affected by solubility/permeability and thus intestinal absorption and oral bioavailability issues. , Therefore, to obtain new oral drugs in this space, molecular properties should be optimized in early drug discovery. , Because property-based drug discovery can be applied at different development stages, both computed and experimental descriptors are required. Recently, we proposed a pool of experimental physicochemical descriptors suitable for quantifying lipophilicity and polarity for bRo5 molecules. , Lipophilicity is efficiently determined using a series of chromatographic descriptors mimicking different environments.…”

“…It was developed as a surrogate of the octanol/water partition coefficient (log D octanol/water) . BRlogD works efficiently in the bRo5 chemical space, and it is crucial for the classification of PROTAC solubility . ElogD is another chromatographic log D octanol/water surrogate developed internally by Pfizer .…”