Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer.

 

Comments:

That's a fascinating discovery! Targeting histone acetyltransferases like KAT6A and KAT6B opens up promising avenues in cancer therapy, particularly in breast cancer cases where KAT6A is frequently amplified or overexpressed.

CTx-648 sounds like an exciting inhibitor with its high potency, selectivity, and oral bioavailability. Its ability to inhibit H3K23 acetylation in KAT6A overexpressing breast cancer cells and subsequently demonstrate anti-tumor activity is significant. The correlation between CTx-648's actions and the inhibition of H3K23 acetylation provides a valuable insight into its mechanism of action.

The transcriptional and epigenetic profiling studies revealing reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc, and stem cell pathways shed light on the intricate mechanisms underlying CTx-648's anti-tumor effects in ER-positive breast cancer. This kind of understanding is crucial for targeted therapies, especially in cases where standard treatments like endocrine therapy are ineffective.

The successful inhibition of tumor growth in ER-positive breast cancer models, even those resistant to endocrine therapy, emphasizes the potential of KAT6A targeting through CTx-648 as a viable therapeutic strategy. This could pave the way for more effective treatments for breast cancer patients, particularly those with resistant or refractory forms of the disease.

Related Products

Cat.No.	Product Name	Information
E0146	PF-9363	PF-9363 is a potent and selective KAT6A/6B inhibitor with Ki of 0.41 nM and 1.2 nM for KAT6A and KAT6B, respectively. PF-9363 displays potent anti-tumor activity in ER+ breast cancer models.

Related Targets

Histone Acetyltransferase