PF-07248144 represents an investigational compound currently under investigation for its potential therapeutic applications. It is being evaluated for its potential to address unmet medical needs.
What is PF-07248144?
PF-07248144 is a small molecule compound under development by Pfizer. The “PF-” prefix in its designation is a standard nomenclature used by Pfizer to identify compounds originating from their research pipeline. This designation indicates that the compound is an investigational drug, not yet received regulatory approval for widespread use.
Specifically, PF-07248144 is classified as a selective catalytic inhibitor of KAT6 (Lysine Acetyltransferase 6), an enzyme involved in various cellular processes. The compound is designed to specifically target and interact with this enzyme. Its development as a small molecule allows for potential oral administration, offering convenience in treatment.
Its Therapeutic Purpose
PF-07248144 is currently being investigated for its use in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. This type of breast cancer is characterized by the presence of estrogen receptors on cancer cells, which can fuel tumor growth, and the absence of HER2 overexpression.
Metastatic breast cancer means the cancer has spread beyond the original tumor site to other parts of the body, making it more challenging to treat. Patients with this condition often experience disease progression even after receiving standard therapies, such as CDK4/6 inhibitors and endocrine therapy. PF-07248144 aims to provide an additional treatment option for these patients, addressing a significant medical need where existing treatments may no longer be effective. The compound seeks to offer a new approach to control cancer cell growth and progression in these advanced cases.
Mechanism of Action
PF-07248144 functions as an inhibitor of KAT6, which includes KAT6A and KAT6B enzymes. These enzymes are a type of histone acetyltransferase (HAT). Histone acetyltransferases add acetyl groups to histone proteins, specifically at lysine residue 23 on histone H3 (H3K23).
This acetylation process leads to a more relaxed chromatin structure, making the DNA more accessible for gene transcription. By inhibiting KAT6, PF-07248144 prevents this acetylation, which can disrupt gene expression. This disruption is particularly relevant in tumors where KAT6 is overexpressed, as it can inhibit the proliferation of these cancer cells. The compound’s interaction with KAT6 aims to induce senescence, a state where cells stop dividing, and to arrest tumor growth, as observed in preclinical studies.
Current Status and Insights
PF-07248144 is currently in advanced stages of clinical development. A pivotal Phase 3 study for PF-07248144 is underway, combining it with fulvestrant (Faslodex). This trial compares the combination therapy against an investigator’s choice of treatment in patients with ER-positive, HER2-negative breast cancer that has progressed after CDK4/6 inhibitor therapy.
Preliminary results from Phase 1 studies have shown encouraging activity and a tolerable safety profile. The 5 mg once-daily dose of PF-07248144 in combination with fulvestrant was identified as an optimal dose, exhibiting an objective response rate (ORR) of 37.2%. The most common treatment-related adverse events observed were mild to moderate dysgeusia (altered taste sensation) and neutropenia (low white blood cell count), which were generally manageable with dose modifications. These findings suggest the compound’s potential efficacy and safety, although it remains an investigational compound not yet approved for commercial use.