Crystallizing the Uncrystallizable: Insights from Extensive Screening of PROTACs

Area of Science:

• Pharmaceutical Science
• Solid-State Chemistry
• Drug Discovery

Background:

• Proteolysis-targeting chimeras (PROTACs) are novel therapeutics beyond the Rule of Five with poor solubility and crystallizability.
• Understanding PROTAC solid-state properties is crucial for preformulation but challenging due to their complex structure.
• No published structures of single-component PROTACs exist to elucidate intermolecular interactions.

Purpose of the Study:

• To determine the solid-state structures of a cereblon-recruiting PROTAC (AZ1).
• To investigate the intermolecular interactions governing PROTAC packing and physical properties.
• To explore potential solid forms and polymorphism in PROTACs.

Main Methods:

• Extensive crystallization screening was employed to obtain single crystals.
• 3D electron diffraction and synchrotron X-ray crystallography were used for structure determination.
• Thermal and spectral characterization identified different solvate forms.

Main Results:

• Single crystals of AZ1 yielded an anhydrous form and a p-xylene solvate.
• Lattice energies were dominated by dispersive interactions, not hydrogen bonds.
• AZ1 demonstrated pseudo-polyamorphism with distinct amorphous solid dissolution characteristics.

Conclusions:

• This work provides the first insight into PROTAC intermolecular interactions in the solid state.
• Dispersive forces play a significant role in packing beyond Rule of Five molecules.
• The findings facilitate solid form screening for challenging bRo5 drug candidates.