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Unlocking WRN: Discovering New Drug Paths for Hard‑to‑Treat Cancers

Fragment-screening

A Fragment‑Based Approach to Target WRN for MSI‑H Cancer Therapy

Microsatellite instability high (MSI-H) cancers, such as uterine and stomach cancer, have faults in their DNA repair systems, making them uniquely dependent on the protein, WRN helicase for survival; if WRN ceases to work, these cancer cells cannot survive.  As healthy (MSS) cells are not WRN dependent, inhibiting WRN offers a high selectivity therapeutic strategy.

However, discovering drug like WRN inhibitors has been very difficult:

  • Helicases have highly conserved ATP binding sites1 - they belong to a family of proteins that look very similar - so drugs often find specificity hard to achieve.
  • The usual approach of high throughput screening (HTS) returns few hits, often non specific or inactive in cells.
  • Some WRN ATP competitive compounds have failed due to impurities or covalent artifacts, not true inhibition.

This study proposes a different method to overcome these roadblocks. Instead of screening huge drug libraries, a team from Merck & Co Inc., and Proteros Biostructures, used fragment-based drug discovery at Diamond. This method detects small, weak-binding chemical fragments that often reveal new, more druggable binding pockets, especially allosteric pockets, which control the protein indirectly.

They combined NMR, SPR and X-ray crystallography to identify weak yet genuine binding fragments and direct visualisation of how these fragments bind WRN.

The study is important to produce selective WRN inhibitors for MSI-H/MMRd cancers with clear therapeutic potential.

Find out what the scientists discovered.

1 a specially shaped pocket on a protein where ATP (adenosine triphosphate) - the cell’s main energy molecule - attaches.

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