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Crystallizing the Un-crystallizable: Insights from Extensive Screening of PROTACs [dataset] Open Access

PROTACs are new drug molecules in the beyond Rule of Five (bRo5) chemical space with extremely poor aqueous solubility and poor crystallizability. This makes PROTACs particularly challenging to understand from a solid-state pre-formulation perspective. 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. An extensive crystallisation protocol was applied to grow single crystals of a cereblon-recruiting PROTAC ‘AZ1’ resulting in structures of an anhydrous form and a non-stoichiometric p-xylene solvate using 3D electron diffraction and synchrotron X-ray crystallography, respectively. The lattice energies are dominated by dispersive interactions between AZ1 molecules despite the presence of multiple hydrogen-bond donors and acceptors and planar aromatic groups, and both structures are built on similar intermolecular interactions. Thermal and spectral characterization revealed another solvate form containing dichloromethane. Amorphous solids produced by mechanochemical grinding of anhydrous AZ1 crystals also differed in dissolution characteristics from an amorphous solid produced by desolvating the dichloromethane solvate crystals, indicating that AZ1 may demonstrate polyamorphism. This study paves the way for solid form screening and understanding in pharmaceutical systems that are far bRo5.

Descriptions

Resource type

Dataset

Contributors

Creator: Steed, Jonathan ¹
Contact person: Steed, Jonathan ¹
Editor: Steed, Jonathan ¹
Data collector: Screen, Martin ¹
Data curator: Screen, Martin ¹
Editor: Screen, Martin ¹

¹ Durham University, United Kingdom

Funder

AstraZeneca
Engineering and Physical Sciences Research Council

Research methods

Other description

Keyword

PROTAC
Polymorphism
Pharmaceuticals
Proteolysis Targeting Chimeras

Subject

Proteolysis
Crystallization

Location

Language

Cited in

Identifier

ark:/32150/r1xg94hp618
doi:10.15128/r1xg94hp618

Rights

Creative Commons Attribution 4.0 International (CC BY)

Publisher

Durham University

Date Created

7/5/25

File Details

Depositor

J.W. Steed

Date Uploaded

7 May 2025, 15:05:09

Date Modified

4 July 2025, 11:07:40

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File format: zip (ZIP Format)

Mime type: application/zip

File size: 1504484218

Last modified: 2025:05:07 16:40:27+01:00

Filename: Data for Understanding the Solid-State Landscape of PROteolysis TArgeting Chimeras.zip

Original checksum: 9b44d809ab34a0ca3dfcfd5d644fc626