An international research collaboration, spearheaded by Pfizer in partnership with Monash University and the Cancer Therapeutics Cooperative Research Centre in Australia, has identified a promising pre-clinical drug candidate with potential anti-tumour activity against Estrogen Receptor (ER) positive breast cancer.
Published in Cell Chemical Biology, the study outlined the discovery of ‘CTx-648,’ a highly potent and orally bioavailable ‘KAT6A/B’ inhibitor.
In mouse models of ER-positive breast cancer, CTx-648 demonstrated significant tumour growth inhibition, showcasing its potential as a groundbreaking therapeutic option.
One of the notable findings is the drug’s effectiveness against tumours resistant to hormone therapy, a standard treatment for ER-positive breast cancer, the university said in a news release.
This discovery also opens up new possibilities for targeting KAT6A in patients with this specific type of breast cancer.
Professor Paul Stupple, director of Medicinal Chemistry at the Monash Institute of Pharmaceutical Sciences (MIPS) and study co-author, expressed his excitement, “The discovery of CTx-648 is incredibly exciting, as it has shown anti-tumour activity in preclinical models of ER-positive breast cancer, including tumours resistant to hormone therapy.”
KAT6A, an enzyme regulating various chemical processes in the body, has been implicated in several cancers, including breast cancer, where the amplification of the KAT6A gene can occur.
Former Chief Scientific Officer of Cancer Therapeutics CRC and now the Director of MedChem Australia at MIPS, Professor Brendon Monahan, highlighted the significance of KAT6A amplification in breast cancer:
“Tumours with KAT6A amplifications are strongly associated with shorter progression-free survival, and overall survival,” said Professor Monahan.
While hormone therapy remains a primary treatment for ER-positive breast cancer, resistance can develop over time, underscoring the need for innovative therapies.
Professor Susan Charman, leading the Centre for Drug Candidate Optimisation at MIPS, emphasised the remarkable properties of CTx-648.
“Compared to previously identified KAT6 inhibitors, CTx-648 represents a marked improvement in potency, selectivity, and drug-like properties,” Charman noted.
The drug demonstrated robust on-target in vivo efficacy in preclinical models, including tumor regressions with minimal toxicities, promising potential for breast cancer patients.
Dr Alan Robertson, managing director of Canthera Discovery, formerly Cancer Therapeutics CRC, highlighted the collaborative effort stating, “This research was a team effort and the collaboration of Cancer Therapeutics CRC partners including Monash University and Pfizer was an example of how multidisciplinary teams working together can have incredible impact.”
The discovery of CTx-648 traces back to research by a team from the Walter and Eliza Hall Institute (WEHI), MIPS, and Cancer Therapeutics CRC in 2018, which explored KAT6A and KAT6B as a novel approach to cancer treatment.
“There is an urgent need for new safe and effective treatments for ER-positive breast cancer, and the team is excited that a KAT6A inhibitor is currently in Phase I clinical trials,” Professor Stupple concluded.
The study was led by Pfizer Research Fellow Dr Shikhar Sharma and Pfizer Senior Director Dr Thomas Paul, with the full list of authors available here.
