First-in-class HSF1 pathway drug shrinks tumours in mice

Cancer research

A new, oral, first-in-class experimental cancer drug has shown potent activity against cancer cells and caused shrinkage of hard-to-treat human ovarian tumours grown in mice, a new study shows.

The drug, which is now called NXP800 and has already entered a Phase I clinical trial, was discovered by scientists at The Institute of Cancer Research, London.

It targets a pathway that cancer cells are highly dependent upon, involving the heat shock factor 1 protein (HSF1).

The new study – which is published in the Journal of Medicinal Chemistry – describes the most advanced stages of the research programme that were required to achieve the final optimised chemical design of the clinical drug itself.

Representing the culmination of a dedicated research mission spanning 15 years, the study demonstrates the promise of the drug to treat a subtype of ovarian cancer that is highly resistant to chemotherapy. It also supports the drug’s potential to treat other cancers.

Mechanism of action

HSF1 is a transcription factor, meaning that it controls the production of other important proteins in the cell, through its regulation of the process of reading the genetic code stored in DNA.

HSF1 is hijacked to support the initiation, growth and progression of cancer cells, including helping cancer cells withstand the stresses they come under as a tumour develops.

However, blocking the activity of transcription factors with drugs is notoriously challenging – and this is especially true of HSF1, which lacks the presence of cavities or ‘pockets’ into which candidate drugs could fit. To overcome this, scientists at the ICR used a method called cell-based phenotypic pathway screening.

NXP800 has been licensed to oncology-focused biopharmaceutical company Nuvectis Pharma, which is leading the further development.

Study lead author Dr Matthew Cheeseman, Senior Staff Scientist at the ICR, said: “We designed the inhibitor using multiparameter optimisation that balanced a range of important properties, such as anti-tumour potency, specificity and safety, with appropriate pharmacokinetic and pharmacodynamic behaviour in our preclinical studies to deliver a new low-dose oral treatment for patients. We hope that our drug goes on to show effectiveness in clinical trials.”

Project leader Professor Paul Workman, Harrap Professor of Pharmacology and Therapeutics at the ICR, added: “Although HSF1 is very challenging to drug directly, we have shown that NXP800 inhibits the HSF1 pathway indirectly through a novel mechanism involving activation of the integrated stress response. We have developed biomarkers to aid our understanding of the drug’s unique molecular mechanism of action and help guide its development in cancer patients.”

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