Addressing the Low Solubility of Proteolysis Targeting
Chimeras Through Solid State Engineering

Abstract

Proteolysis-targeting chimeras (PROTACs) represent a promising drug modality within the beyond Rule of Five (bRo5) chemical space but are hindered by extremely poor aqueous solubility and limited crystallisability, due to their flexible structures consisting of two ligand moieties joined chemically by a linker. While several X-ray structures have been reported of PROTACs in ternary complexes, to date no structures have been published of single-component densely packed PROTACs, from which an understanding of PROTACs’ intermolecular interactions, and therefore physical properties, can be developed. This thesis addresses these challenges through solid-state engineering approaches aimed at improving solubility and advancing pre-formulation strategies. The first single-component crystal structures of a cereblon-recruiting PROTAC ‘AZ1’ are reported, obtained via advanced crystallisation protocols combined with 3D electron diffraction and synchrotron X-ray diffraction. Despite their potential for hydrogen bonding, these structures are dominated by dispersive interactions, forming similar packing motifs across different crystalline forms. Generating amorphous phases of AZ1 by different methods can lead to distinct dissolution behaviours, suggesting that PROTACs can also exhibit pseudo-polyamorphism. Pre-formulation studies show that amorphous solid dispersions (ASDs) of PROTACs with HPMCAS polymer significantly enhance supersaturation upon dissolution compared to the pure amorphous drug, achievable at a relatively high weight-percentage of drug when synthesised via the slurry conversion method. In contrast, co-amorphous systems with small molecule co-formers failed to improve dissolution despite evidence of inter-component hydrogen bonding. Complementary crystallisation studies on lenalidomide, a molecular fragment of AZ1, explore low-solubility co-crystals for pulmonary drug delivery and gel-phase crystallisation to control polymorphism, highlighting novel avenues for managing solid state properties. Collectively, these findings contribute towards an understanding of how to overcome PROTACs’ poor pharmacokinetic properties through tailored solid-state strategies.