Dr James Kaduk | Mapping a Cancer Drug’s Structure Towards Better Drug Development

In a recent study, the team packed a tiny sample of the powdered drug into a tube less than half a millimetre wide, then bombarded it with high-intensity X-rays at the Canadian Light Source – one of the most powerful X-ray sources in the world.

The way the X-rays bounce off the crystalline material produces a distinctive pattern of peaks and signals, which the researchers then painstakingly interpreted to reconstruct the three-dimensional arrangement of atoms within the crystals.

The crystal structure of a drug affects almost everything about how it behaves as a medicine – its stability, how readily it dissolves, how well it is absorbed by the body, and how it can be manufactured consistently at scale. Two versions of a drug with identical chemical formulas but different crystal structures can behave very differently in the body. For drug developers and regulators, having an accurate, publicly available reference structure is therefore a crucial resource.

Kaduk’s team found that repotrectinib forms neat stacks of V-shaped molecules, linked together by hydrogen bonds into chains.

To double-check that the structure they had mapped was physically plausible, the team also modelled it computationally, using software to simulate how the atoms would naturally settle given the forces acting between them. The experimentally observed structure and the computer-predicted structure matched closely – a reassuring sign that the result is correct.

The structural data have now been added to the Powder Diffraction File, published by the International Centre for Diffraction data, which is used by researchers, drug developers, and manufacturers around the world as a reference resource. Having this information freely available means that other scientists working with repotrectinib – whether studying its behaviour, developing generic versions, or investigating how it might be improved – no longer have to start from scratch.

It is painstaking, highly technical work that rarely makes headlines. But studies like this one, quietly mapping the molecular architecture of the medicines we rely on, form an essential part of the scientific infrastructure underpinning modern drug development.