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 particular 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 too.

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 our 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. It is linked to the clinical outcome of several different cancer types.

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’ that candidate drugs could fit into.

To overcome this, scientists at The Institute of Cancer Research (ICR) – based in its Centre for Cancer Drug Discovery – initiated the project using a carefully chosen experimental approach, involving a method called cell-based phenotypic pathway screening.

The researchers established a cellular imaging technique that read out the activity of the HSF1 pathway in cancer cells. This enabled them to screen a library of chemical compounds to discover a series of small molecules, called bisamides, that blocked the pathway and inhibited cancer cell growth, without necessarily targeting HSF1 directly.

The new research was largely funded by Cancer Research UK, the Cancer Research Pioneer Fund (CPF) and the Battle Against Cancer Investment Trust (BACIT). In the study, the researchers describe an elegant programme of scientific research to optimise molecules from this bisamide chemical series and create the clinical drug, which they initially called CCT361814.

It has since been licensed to oncology-focused biopharmaceutical company Nuvectis Pharma, which is leading the further development of the drug, now re-named as NXP800.

A critical aspect of the design of this new clinical drug was the simultaneous optimisation of several key properties, often involving some careful compromise between different competing priorities.

One important focus of this multiparameter compound optimisation research carried out by the ICR team was to reduce the speed of its active removal from cells, through a process called P-glycoprotein efflux.

This efflux can cause problems with achieving adequate cellular concentrations of drugs and cause too rapid clearance of drugs from the body which can limits anticancer activity. Efflux can also lead to multi-drug resistance, which commonly occurs in ovarian and other cancers.

The ICR scientists solved this P-glycoprotein efflux problem by adding a fluorine atom to one the compound’s central rings. Experiments in mice with tumours grown from human ovarian cancer cells showed that the new fluoro-bisamide drug caused impressive and sustained tumour regression.

The researchers demonstrated the drug’s anti-tumour effectiveness when administered orally to mice, mimicking a clinical tablet or capsule.

Another important feature of the new study was the use of molecular biomarkers to demonstrate that the NXP800 drug was indeed inhibiting the HSF1 pathway in the human ovarian tumours in mice, through activation of a connected cell signalling pathway, called the integrated stress response.

Using these molecular biomarkers enabled the study to follow the principles of the Pharmacological Audit Trail – an approach developed by the ICR researchers to ensure that a drug is working through its intended mechanism and also to help predict the dose to be used in human patients. This biomarker-led approach is also now being applied in the ongoing clinical trial.

Further studies established the predicted safety of the drug, with no effects of concern detected across a panel of pharmacological safety tests.

Study lead author Dr Matthew Cheeseman, Senior Staff Scientist at the ICR, said:

“We’re pleased to publish the details of the discovery of our first-in-class HSF1 pathway inhibitor. In this study, we demonstrate the clear potential of our drug as a cancer treatment, which led to its first clinical trial.

“The discovery of this drug required us to overcome many challenges in medicinal chemistry, including reducing its clearance from cancer cells via P-glycoprotein efflux, which could otherwise have led to problems with drug resistance. 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, said:

“The HSF1 pathway oversees the expression of a range of genes involved in cancer initiation and development and is dysregulated in many cancer types. Our new study is the culmination of a decade and a half of research to discover a small-molecule inhibitor of the HSF1 pathway suitable for clinical trial, and we’re proud to now describe the successful outcome of this with the discovery of NXP800 – a potent, orally active HSF1 pathway inhibitor – and to demonstrate its exciting potential as a future treatment for a range of cancers, including a subtype of ovarian cancer that is commonly resistant to current chemotherapy.

“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.”

Professor Kristian Helin, Chief Executive at the ICR, said:

“Our HSF1 programme is a great example of the type of innovative, long-term, high-quality drug discovery research that we run in the ICR’s Centre for Cancer Drug Discovery. It is part of our role in the research ecosystem to carry out such high-risk, high-reward research which is essential if we are to make real impact for cancer patients. We have been committed to drugging this important but difficult target for the long haul.

“We are delighted that in collaboration with an industry partner in Nuvectis and our hospital partner The Royal Marsden, NXP800 has now entered clinical trials, as one of 13 candidates we’ve discovered in the past two decades to reach the clinic – and we hope to see it have a major impact in the future by becoming a new treatment, for the patients who so urgently need it.”

Source: ICR