KAT6A (Lysine Acetyltransferase 6A)

We extensively benchmark key compounds from each chemotype, augmented by new acylsulfonohydrazide analogues and a novel fused [1,2,4]thiadiazine KAT6A inhibitor subclass, which we report here for the first time, along with co-crystal structures. Additionally, we report on the in vivo activity, pharmacokinetics, and toxicology profiles of these inhibitors.

PF-07248144 has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer models and is currently undergoing clinical evaluation...This review provides a comprehensive overview of the structural and biological functions of KAT6A, its role in tumor progression, and the therapeutic potential of its inhibition. It summarizes the advancements in KAT6A inhibitor development from 2019 to the present, emphasizing the optimization processes from lead compounds to clinical candidates.

Treatment with CTx-648, a KAT6A/KAT6B inhibitor, restored HSC function in Phf6R274XTg mice and prolonged the survival of leukemic Phf6R274XTg mice. These findings demonstrate a gain-of-function effect for truncated PHF6aa1-273 in driving leukemogenesis and highlight KAT6B as a promising therapeutic target in PHF6 truncation-associated hematologic malignancies.

To establish the efficacy of MYST inhibition in vivo , we treated mice harboring a syngeneic SETBP1 -mutant leukemia with the clinical-grade MYST inhibitor-PF-9363...In this study, we identify MYST acetyltransferases as key drivers of mutant SETBP1-driven transcription. MYST inhibitors are highly effective against SETBP1-mutant leukemia and represent a promising avenue for clinical translation.

KAT6A promotes the proliferation of CC cells and suppresses ferroptosis via epigenetic regulation of GPX4. Our work presented KAT6A as a potential diagnostic and therapeutic target for treatment CC.

We discuss preclinical evidence supporting the therapeutic potential of KAT6 inhibition and the challenges faced in epigenetic drug development, including the need for robust biomarker-driven approaches. Finally, we explore the prospects for integrating KAT6 inhibitors with existing therapies to overcome resistance and improve patient outcomes in breast cancer.

In this review, we summarize the currently available information regarding the physiological and pathological functions of KAT6A and KAT6B and discuss their potential as antitumor targets in drug development. We also present the discovery and development of an emerging class of KAT6 inhibitors under investigation for breast cancer, along with potential molecular mechanisms underlying the therapeutic efficacy of targeting KAT6, providing references for developing therapeutic strategies in clinical practice.

It also investigates interactions between KATs and Tumor-associated signalling pathways, with a focus on emerging KAT inhibitors and their clinical progress. The aim is to provide a theoretical basis and direction for future research into epigenetic therapeutic strategies for cancer.

Collectively, our research demonstrated that KAT6A upregulates BRD1 protein expression through acetylation, thereby promoting CRC progression. These results suggest KAT6A-mediated BRD1 acetylation as a novel and promising therapeutic target for CRC, contributing valuable insights into the molecular mechanisms underlying CRC pathogenesis.

Overexpression of either Tet1 or TRPV4 rescued the KAT6A knockdown-induced osteoclast differentiation inhibition. KAT6A promotes osteoclast differentiation through a regulatory cascade involving Tet1-mediated TRPV4 upregulation, which identifying KAT6A as a potential therapeutic target for osteoporosis treatment.

The future of breast cancer therapy lies in combination strategies that are developed via molecular profiling and guided by resistance biomarkers. Integrative, biomarker-driven treatment approaches will provide a rationalized and likely more effective means of treating advanced and refractory breast cancer in our effort to improve patient outcomes in a targeted and personalized approach.

Finally, we benchmark the activity of PF-9363 in the NCI-60 cell line screen, providing evidence that it can inhibit the growth of cell lines that are resistant to other epigenetic inhibitors by engaging the essential MYST enzyme KAT8 at high concentrations. Collectively, our studies indicate the potential for MYST KAT inhibitors to exhibit dose-dependent target engagement reminiscent of kinase inhibitors and specify assays and biomarkers for facile monitoring of selective and hierarchical effects.