ICR Scientists Develop Pathfinder Molecules Targeting DHX8 in Cancer Drug Discovery

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(IN BRIEF) Researchers at The Institute of Cancer Research, London, working with Merck KGaA, have developed the first potent small-molecule inhibitors of DHX8, an enzyme involved in pre-mRNA splicing. The compounds are described as “pathfinder molecules” rather than drug candidates, but they show that DHX8 and potentially other DEAH-box RNA helicases can be blocked by interfering with their interaction with RNA. The research builds on earlier ICR work showing that DHX8 helps cancer cells manage stress and survive hostile conditions by supporting production of HSF1, a key stress-response regulator. Using fragment-based drug design, the team screened nearly 2,000 fragments, identified four that competed with RNA binding, and developed one weak fragment into highly potent inhibitors, including compound 53, which showed target engagement in lung cancer cells.

(PRESS RELEASE) LONDON, 7-Aug-2026 — /EuropaWire/ — The Institute of Cancer Research (ICR) has taken an important step toward targeting a largely underexploited family of potential cancer drug targets by developing the first potent small-molecule inhibitors of DHX8, an enzyme involved in pre-mRNA splicing, a fundamental process in human cells.

The work was carried out by scientists at the ICR in collaboration with Merck KGaA, with funding from Cancer Research UK.

The findings, published in the Journal of Medicinal Chemistry, show for the first time that members of the DEAH-box family of RNA helicases can be inhibited by small molecules that interfere with their ability to interact with RNA.

The researchers describe the compounds as “pathfinder molecules” because they are not yet drug candidates and are not sufficiently advanced to be considered chemical probes.

However, they provide a valuable starting point for designing future inhibitors that target DHX8 and potentially other RNA helicases in the DEAH-box family.

RNA splicing takes place after DNA has been copied into messenger RNA, or mRNA.

During this process, non-coding sections are removed and coding sections are joined together to create the final genetic message that is translated into protein.

Splicing can vary which RNA sections are removed or retained, allowing a single gene to produce multiple proteins.

This increases the diversity of proteins available to cells.

In healthy cells, splicing is tightly regulated.

In cancer cells, however, the process can be hijacked, helping tumours increase their diversity, evolve and develop resistance to treatment.

The latest study builds on earlier work from the ICR’s Centre for Cancer Drug Discovery, which identified DHX8 as an important regulator of how cancer cells cope with stress and survive in hostile environments.

That earlier research showed that blocking DHX8 disrupted the production of HSF1, a master regulator that helps cancer cells adapt to the many stresses they face as they grow and spread under the influence of cancer-driving oncogenes.

DHX8 belongs to the RNA helicase family, a group of molecular machines that help bind, remodel and unwind RNA inside cells.

These proteins play essential roles in gene expression but have long been considered difficult to target because they are highly dynamic and share structural similarities with related family members.

DHX8 is also an essential component of the spliceosome, the large molecular machinery responsible for cutting and joining RNA.

Within the spliceosome, DHX8 helps ensure the correct splicing and release of finished RNA so that it can be translated into protein.

The ICR team had previously created an important foundation for the project by determining the crystal structure of the helicase domain of human DHX8.

Combined with evidence that DHX8 helps drive cancer stress responses, this gave researchers a rare opportunity to explore the enzyme as a possible therapeutic target.

To identify compounds capable of blocking DHX8 function, the team used fragment-based drug design.

This approach begins with very small chemical fragments that bind weakly to a target protein.

Scientists then use detailed three-dimensional structural information to understand how the fragments interact with the protein and gradually build them into stronger inhibitors.

In this study, the researchers screened nearly 2,000 fragments against DHX8.

Only four fragments were found to compete with RNA for binding to the protein.

The team selected one particularly promising fragment for further development.

Although it initially bound only weakly to DHX8, structural studies revealed interaction details that made it a strong candidate for optimisation.

Using X-ray crystallography and structure-guided medicinal chemistry, the researchers modified the fragment over multiple rounds of design and testing.

The resulting compounds became thousands of times more potent than the original fragment.

The optimisation process ultimately produced molecules that inhibited DHX8 activity at nanomolar concentrations in biochemical tests using purified protein.

The study also explains how the new molecules act on DHX8.

Rather than binding to the enzyme’s energy-generating site, they occupy part of a tunnel through which the RNA strand passes.

By blocking this tunnel, the molecules prevent RNA movement and lock DHX8 into an inactive shape, stopping it from performing its normal splicing and RNA-processing role.

The researchers also found evidence that the pathfinder molecules can bind DHX8 in live human cancer cells.

This is an important step in showing that the compounds can engage the target within a cellular environment.

The strongest-performing molecule, known as compound 53, demonstrated both strong biochemical activity and measurable target engagement in lung cancer cells.

The researchers emphasised that much more work is required before therapeutic applications can be considered.

Future research will need to assess whether DHX8 inhibitors can provide a cancer-selective therapeutic window and investigate the potential side effects of more advanced compounds.

Even so, the findings provide a foundation for developing improved research tools to study DHX8 and other DEAH-box RNA helicases in health and disease.

The project brought together expertise in cancer biology, medicinal chemistry, structural biology and drug discovery.

Scientists from the ICR’s Centre for Cancer Drug Discovery identified DHX8 as a cancer target and carried out key structural studies that supported the inhibitor programme.

Researchers at Merck KGaA contributed additional small-molecule drug discovery expertise, helping accelerate optimisation of the pathfinder compound.

Dr Rob van Montfort, Group Leader of the Hit Discovery and Structural Design Group at the ICR, and project leader and co-corresponding author, said the study demonstrates for the first time that potent RNA-competitive DEAH-box helicase inhibitors can be developed.

He said the findings suggest it may be possible to target the broader family of 14 RNA helicases, which had previously been regarded as difficult or even impossible to drug with small-molecule inhibitors.

Dr van Montfort added that it is particularly significant that the potent inhibitors originated from extremely small fragments that initially interacted only weakly with DHX8.

He said the work demonstrates the value of fragment-based drug design for addressing targets that have traditionally been considered very difficult to drug.

Through this research, the ICR and its collaborators have opened a new route for exploring DHX8 and related RNA helicases as potential cancer drug targets, while providing early molecular tools that could support future drug discovery in an underexplored area of cancer biology.

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SOURCE: The Institute of Cancer Research