Advancements in HSF1 Pathway Inhibition: The Development and Clinical Progress of NXP800

The study introduces NXP800, a novel HSF1 pathway inhibitor developed at the Institute of Cancer Research, London, and its advancement to Phase I clinical trials in partnership with Nuvectis Pharma. HSF1, a crucial transcription factor in the heat shock response, is exploited by cancer cells to activate specific genes, which is linked to cancer development and progression. Despite its significance in cancer, HSF1's role in non-stressed conditions is limited, suggesting a therapeutic opportunity. HSF1's involvement in various cancers has been indicated by its gene amplification and expression, which predict clinical outcomes.

The development of HSF1 inhibitors faced challenges due to the protein's complex structure. However, an initial screen targeting the HSF1-regulated gene HSP72 led to the discovery of the bisamide series. Through structure-activity studies and medicinal chemistry, NXP800 was selected for development. It demonstrates favorable pharmacokinetics and modulates biomarkers in human tumor models, showing therapeutic efficacy in specific ovarian cancers with unmet medical needs.

NXP800 has shown significant anti-tumor activity, tumor growth inhibition, and regression at well-tolerated doses, indicating a therapeutic window. The drug's selectivity and safety are supported by pharmacology and kinome panel data. Furthermore, an association between ARID1A deficiency and increased therapeutic response to NXP800 was identified, suggesting potential in treating additional cancer types.

Supporting the mechanism of action and patient biomarker identification, a Phase 1 trial for NXP800 is underway, incorporating predictive and pharmacological biomarkers to ensure a comprehensive evaluation and dosage prediction for human use.