Discovery of drug candidate to potentially tackle ER-positive breast cancer

  • Around 2.3 million people are diagnosed with breast cancer globally each year.
  • Dysregulation of an enzyme called ‘KAT6A’ has been observed in some ER-positive breast cancers, leading to adverse patient outcomes. However the discovery of drugs to target KAT6A for therapeutic benefit has remained a challenge.
  • The discovery of ‘CTx-648’ presents a new opportunity to target KAT6A in ER-positive breast cancer.

An international team of researchers, led by Pfizer in collaboration with Monash University and the Australian-based Cancer Therapeutics Cooperative Research Centre, have discovered a pre-clinical drug candidate demonstrating anti-tumour activity in Estrogen Receptor (ER) positive breast cancer models.

The study, published in Cell Chemical Biology, describes the identification of a highly potent, selective and orally bioavailable ‘KAT6A/B’ inhibitor called ‘CTx-648’ which led to promising tumour growth inhibition in ER-positive breast cancer models in mice.

The team of researchers also found CTx-648 treatment led to anti-tumour activity in tumours resistant to hormone therapy, a common line of treatment for ER-positive breast cancer patients. As such, the discovery of CTx-648 presents an exciting new opportunity to target KAT6A in patients with ER-positive breast cancer.

Director of Medicinal Chemistry at the Monash Institute of Pharmaceutical Sciences (MIPS) and study co-author Professor Paul Stupple said, “The discovery of CTx-648, a potent, selective, and orally bioavailable KAT6A inhibitor, which has shown anti-tumor activity in preclinical models of ER-positive breast cancer, including tumours resistant to hormone therapy, is incredibly exciting.

“KAT6A is an enzyme that helps to regulate a wide variety of chemical processes in the body. However, dysregulation of KAT6A has been identified in several cancers, including breast cancer where amplification of the KAT6A gene can occur,” Professor Stupple said.

Former Chief Scientific Officer of Cancer Therapeutics CRC and now the Director of MedChem Australia which sits within MIPS, Professor Brendon Monahan, commented “KAT6A amplification in breast cancer is associated with poor overall survival, with analysis of breast cancer patient datasets indicating KAT6A amplifications occur in 6–11 percent of tumours.

“Tumours with KAT6A amplifications are strongly associated with shorter progression-free survival, and overall survival,” said Professor Monahan.

“Hormone therapy remains the backbone for treatment of ER-positive breast cancer patients, however resistance to this line of therapy eventually develops, highlighting the need for novel therapies to target such tumours.”

The team from the Centre for Drug Candidate Optimisation which is one of the five research themes within MIPS and led by Professor Susan Charman, played a critical role profiling the physicochemical, metabolic and pharmacokinetic properties of candidate compounds to inform medicinal chemistry design strategies for compound optimisation.

Professor Charman said “Compared to previously identified KAT6 inhibitors, CTx-648 represents a marked improvement in potency, selectivity, and drug-like properties.

“CTx-648 has demonstrated robust on-target in vivo efficacy in pre-clinical models, including tumour regressions, with minimal toxicities, highlighting the promise of this novel therapy in treating breast cancer patients,” said Professor Charman.

Dr Alan Robertson, Managing Director of Canthera Discovery formally Cancer Therapeutics CRC said “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.”

It was research led by a team from WEHI, MIPS and Cancer Therapeutics CRC that originally paved the way for the discovery of CTx-648 through their investigation into whether KAT6A and KAT6B could be a new approach to treating cancer. The study was published in Nature in 2018.

CTx-648, subsequently invented by MIPS researchers in 2018, was part of multi-million dollar licensing deal to Pfizer by the Cancer Therapeutics CRC and led to drug candidate PF-07248144, which entered Phase I clinical trials in 2020.

“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,” said Professor Stupple.

This study was led by Pfizer Research Fellow, Dr Shikhar Sharma and Dr Thomas Paul, a Senior Director at Pfizer. The MIPS team includes drug researchers from Medicinal Chemistry and the Centre for Drug Candidate Optimisation. The full list of authors can be found here.

ENDS

About the Monash Institute of Pharmaceutical Sciences
MIPS houses over 450 researchers and graduate students across five major themes of activity in Pharmaceutical Sciences – Drug Discovery Biology, Medicinal Chemistry, Drug Candidate Optimisation, Drug Delivery, Disposition and Dynamics and Medicine Use and Safety. Therapeutically, MIPS strengths lie in neuroscience and mental health, cardiovascular and metabolic health, and global health. Major capabilities lie in G-protein coupled receptor (GPCR) biology, synthetic medicinal chemistry, fragment-based drug design, ADME-informed lead optimisation, drug formulation and delivery (including nanomedicine), and optimised medicine use and safety in community and clinical settings. MIPS is committed to research translation and industry engagement and recent successes include the spin out/start-up companies Cincera, Septerna, Ankere and Inosi and significant ongoing relationships with local and international companies including Takeda, Servier, CSL, Starpharma, PureTech and Polyactiva.

About Cancer Therapeutics CRC
Cancer Therapeutics CRC was an oncology focused small molecule drug discovery and early development biotechnology group, established under the Australian government’s Cooperative Research Centre initiative. CTx’s unique partnership model leveraged the capabilities and expertise of its Industry Participants with those of a number of Australia’s pre-eminent Medical Research Institutes and Universities. CTx’s Participants were the Children’s Cancer Institute, CSIRO, Griffith University, Monash University, Peter MacCallum Cancer Centre, WEHI, St Vincent’s Institute of Medical Research, SYNthesis Research, CTxONE (now Oncology One), National Cancer Centre Singapore, Clinical Genomics, Cancer Trials Australia, Medicines Development for Global Health Limited, Cancer Council of Victoria, Syneos Health, Melbourne Health (now Royal Melbourne Hospital) and the Victorian Comprehensive Cancer Centre. The management company for Cancer Therapeutics CRC has become Canthera Discovery.