Discovery of a drug candidate to potentially fight ER-positive breast cancer

An international team of researchers, led by Pfizer in collaboration with Monash University and the Cancer Therapeutics Cooperative Research Center based in Australia, has discovered a preclinical drug candidate demonstrating anti-tumor activity in d-receptor-positive breast cancer models. estrogen (ER).

The study, published in Cellular chemical biologydescribes the identification of a highly potent, selective and orally bioavailable “KAT6A/B” inhibitor, called “CTx-648”, which led to promising inhibition of tumor growth in ER- breast cancer models. positive in mice.

The research team also found that CTx-648 treatment resulted in antitumor activity in tumors resistant to endocrine therapy, a common line of treatment for patients with ER-positive breast cancer. 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 co-author of the study, Professor Paul Stupple, said: “The discovery of CTx-648, a potent, selective and bioavailable KAT6A inhibitor orally, which showed antitumor activity. in preclinical models of ER-positive breast cancer, including tumors resistant to hormone therapy, is incredibly exciting.

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

Former Scientific Director of Cancer Therapeutics CRC and now Director of MedChem Australia who sits on MIPS, Professor Brendon Monahan, commented: “KAT6A amplification in breast cancer is associated with poor overall survival, l Analysis of breast cancer patient datasets indicating that KAT6A amplifications occur in 6-11% of tumors.

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

“Hormone therapy remains the backbone of treatment for patients with ER-positive breast cancer, but resistance to this line of treatment eventually develops, highlighting the need for new treatments to target these tumors.”

The team at the Center for Optimization of Drug Candidates, one of five research themes at MIPS and led by Professor Susan Charman, has played a vital role in profiling the physicochemical, metabolic and pharmacokinetic properties of candidate compounds in order to ‘illuminate medicinal chemistry design strategies for compound optimization. .

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

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

Dr Alan Robertson, Managing Director of Canthera Discovery, formerly Cancer Therapeutics CRC, said: “This research was the result of 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 by a team from WEHI, MIPS and Cancer Therapeutics CRC that initially paved the way for the discovery of CTx-648 through their investigation into whether KAT6A and KAT6B could provide 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 a multimillion-dollar licensing deal with Pfizer by the Cancer Therapeutics CRC and led to the drug candidate PF-07248144, which is 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 a phase I clinical trial,” Professor Stupple said.