An international team of researchers, led by Pfizer in collaboration with Monash University and the Australian-based Cancer Therapeutics Cooperative Research Center, has made a significant breakthrough in tackling Estrogen Receptor (ER) positive breast cancer. The team has discovered a pre-clinical drug candidate that exhibits anti-tumor activity in models of ER-positive breast cancer.
The research, which was published in Cell Chemical Biology, focuses on the identification of CTx-648, a highly potent and selective inhibitor of the KAT6A/B enzyme. CTx-648 has shown promising results in inhibiting tumor growth in mice models of ER-positive breast cancer.
One notable finding from the study is that CTx-648 is effective in tumors that have developed resistance to hormone therapy, a common treatment for ER-positive breast cancer patients. This discovery presents a new opportunity to target KAT6A in patients with this type of breast cancer.
Professor Paul Stupple, Director of Medicinal Chemistry at the Monash Institute of Pharmaceutical Sciences and co-author of the study, expressed his excitement about the discovery of CTx-648. He emphasized that this potent and orally bioavailable inhibitor has demonstrated anti-tumor activity in pre-clinical models, including hormone therapy-resistant tumors.
The enzyme KAT6A, which is regulated by CTx-648, plays a role in various chemical processes in the body. However, dysregulation of KAT6A has been identified in several cancers, including breast cancer. Amplification of the KAT6A gene has been observed in 6%-11% of breast tumors and is associated with poor overall survival.
Hormone therapy remains the standard treatment for ER-positive breast cancer patients. However, resistance to this therapy eventually develops, highlighting the need for novel therapeutic strategies. The discovery of CTx-648 offers new hope for effectively targeting tumors that have become resistant to hormone therapy.
The team of researchers from the Center for Drug Candidate Optimization, led by Professor Susan Charman at MIPS, played a crucial role in analyzing the properties of CTx-648. Their findings informed the design strategies for compound optimization.
Compared to previously identified KAT6 inhibitors, CTx-648 demonstrates improved potency, selectivity, and drug-like properties. In pre-clinical models, CTx-648 has shown robust efficacy with tumor regressions and minimal toxicities, suggesting its potential as a novel therapy for breast cancer patients.
Dr. Alan Robertson, Managing Director of Canthera Discovery, commented on the collaborative efforts of Cancer Therapeutics CRC partners, including Monash University and Pfizer, and their impact on the research. This joint effort led to the discovery of CTx-648, building upon previous investigations into KAT6A and KAT6B as potential targets for cancer treatment.
CTx-648 was invented by MIPS researchers in 2018 and subsequently licensed to Pfizer as part of a multi-million dollar deal with the Cancer Therapeutics CRC. It has since become the drug candidate PF-07248144, which entered Phase I clinical trials in 2020.
Professor Stupple acknowledged the urgent need for safe and effective treatments for ER-positive breast cancer. He highlighted the team’s excitement about the Phase I clinical trials of a KAT6A inhibitor, such as CTx-648, as a potential breakthrough in addressing this pressing medical need.
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
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