Chemistry:Prifetrastat
Prifetrastat (development code PF-07248144) is an investigational oral epigenetic drug developed by Pfizer for the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer.[1]
The drug is a first-in-class selective inhibitor of the histone acetyltransferases KAT6A and KAT6B, enzymes that regulate gene transcription through histone acetylation at lysine 23 (H3K23).[1] Prifetrastat has shown promising results in early clinical trials, particularly when combined with fulvestrant, in patients whose disease has progressed after treatment with CDK4/6 inhibitors and endocrine therapy. As of 2025, the compound is being evaluated in Phase 3 clinical development.[2]
Medical uses
Prifetrastat is being investigated for the treatment of patients with estrogen receptor-positive (ER+), HER2-negative metastatic breast cancer, particularly those who have experienced disease progression following treatment with a CDK4/6 inhibitor and at least one line of endocrine therapy.[1][3]
Mechanism of action
Prifetrastat functions as a potent and selective catalytic inhibitor of the histone lysine acetyltransferases KAT6A and KAT6B.[1] These enzymes are members of the MYST family of acetyltransferases and play crucial roles in regulating gene expression by adding acetyl groups to histone H3 at lysine 23 (H3K23), as well as to other non-histone substrates.[1]
KAT6A is located on chromosome 8 and is amplified in approximately 10-15% of patients with ER-positive breast cancer.[4] KAT6A amplification has been associated with the ability to repress estrogen receptor gene transcription, thereby contributing to resistance to endocrine therapy, particularly in the context of ESR1 mutations. By inhibiting KAT6A and KAT6B, prifetrastat suppresses estrogen receptor expression and overcomes resistance mechanisms that limit the efficacy of standard endocrine therapies.[1]
In preclinical studies, prifetrastat demonstrated potent antitumor activity in ER-positive, HER2-negative patient-derived xenograft (PDX) models that had been pretreated with palbociclib and letrozole, suggesting the compound's ability to overcome acquired resistance to CDK4/6 inhibitors, which is under investigation.[4]
Clinical development
Phase 1 study
An ongoing Phase 1 study (NCT04606446) is a multicenter, open-label dose escalation and expansion trial designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of prifetrastat as monotherapy and in combination with other anticancer agents.[3] As of 2024, interim results from multiple completed cohorts have been reported in peer-reviewed publications and at scientific conferences.[1][5]
Phase 3 development
Based on the Phase 1 results, Pfizer has advanced prifetrastat to a Phase 3 trial to evaluate prifetrastat in combination with fulvestrant in patients with HR+/HER2- metastatic breast cancer who have progressed following treatment with a CDK4/6 inhibitor and endocrine therapy.[5][6]
See also
- Breast cancer
- Estrogen receptor
- Epigenetics
- Histone acetyltransferase
- Fulvestrant
- CDK4/6 inhibitor
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Inhibition of lysine acetyltransferase KAT6 in ER+HER2- metastatic breast cancer: a phase 1 trial". Nature Medicine 30 (8): 2242–2250. August 2024. doi:10.1038/s41591-024-03060-0. PMID 38824244.
- ↑ "Delving into the Latest Updates on Prifetrastat with Synapse". https://synapse.patsnap.com/drug/41fbdd069c3544ac99cade2647811623.
- ↑ 3.0 3.1 A Phase 1/2A Dose Escalation and Expansion Study to Evaluate Safety, Tolerability, Pharmacokinetic, Pharmacodynamic, and Anti-tumor Activity of PF-07248144 in Participants With Advanced or Metastatic Solid Tumors. 12 August 2025. NCT04606446. https://clinicaltrials.gov/study/NCT04606446. Retrieved 12 November 2025.
- ↑ 4.0 4.1 "KAT6 Inhibition Shows Path to Overcoming Resistance Mechanisms in ER+ Breast Cancer". September 18, 2025. https://www.onclive.com/view/kat6-inhibition-shows-path-to-overcoming-resistance-mechanisms-in-er-breast-cancer.
- ↑ 5.0 5.1 "Dose optimization of PF-07248144, a first-in-class KAT6 inhibitor, in patients (pts) with ER+/HER2− metastatic breast cancer (mBC): Results from phase 1 study to support the recommended phase 3 dose (RP3D)". 2025 ASCO Annual Meeting. May 2025. doi:10.1200/JCO.2025.43.16_suppl.1020. Abstract 1020. https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.1020.
- ↑ Pfizer (2026-04-15). An Interventional, Open-Label, Randomized, Multicenter, Phase 3 Study of PF-07248144 Plus Fulvestrant Compared to Investigator's Choice of Therapy in Adult Participants With Hormone Receptor-Positive, HER2-Negative Advanced/Metastatic Breast Cancer Whose Disease Progressed After Prior CDK4/6 Inhibitor-based Therapy (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT07062965.
External links
- Clinical Trials Information at Clinical Trials
- Phase 1 Trial Publication at Nature Medicine
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