CTx-648 / Pfizer, Cancer Therapeutics CRC - LARVOL DELTA

The Histone Acetyltransferase MOZ (KAT6A) Is a Molecular Dependency and Therapeutic Target in NUP98-Rearranged Acute Myeloid Leukemia (ASH 2024) - "In combination with SNDX-5613, PF9363 increased median latency by 50% compared to vehicle and by 18% compared to PF9363 alone. In summary, our studies show that MOZ is a therapeutic vulnerability in NUP98 FO-driven AML and that MOZ inhibitor treatment may improve responses to Menin inhibition."

Epigenetic controller • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • HOXA13 • HOXA9 • JADE2 • KAT6A • KDM5A • KMT2A • MEIS1 • NSD1 • NUP98 • PRRX1 • SETBP1

Hierarchical small molecule inhibition of MYST acetyltransferases. (PubMed, bioRxiv) - "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."

Journal • Breast Cancer • Oncology • Solid Tumor • KAT6A • KAT8

KAT6A/B inhibition synergizes with retinoic acid and enhances the efficacy of GD2-targeted immunotherapy in neuroblastoma. (PubMed, bioRxiv) - "Moreover, PF-9363 plus retinoids increases GD2 expression, rendering neuroblastoma cells more sensitive to anti-GD2 immunotherapy. Overall, our studies demonstrate that KAT6A/B inhibition increases the effectiveness of retinoids and GD2-targeted immunotherapy in neuroblastoma."

IO biomarker • Journal • Neuroblastoma • Oncology • Solid Tumor • GATA3 • HOXB6 • KAT6A • MYCN • PHOX2B

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia. (PubMed, Cancer Discov) - "Here we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in range of AML models showing that although KAT6A/B inhibition is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, markedly increases efficacy...Combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Notably, KAT7 remains an important targetable dependency in acquired genetic/non-genetic resistance to Menin inhibition providing the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KAT6A • KAT6B

MUTATIONS IN SETBP1 DRIVE GRANULOCYTE LINEAGE OUTPUT AND LEUKEMOGENESIS VIA KAT7-MEDIATED EPIGENETIC MODULATION AND TRANSCRIPTIONAL REPROGRAMMING (EHA 2025) - "To explore the functional role of these proteins on epigenetic modulation, KAT6A/KAT7 inhibitors (CTX-648, WM-3835) were tested in SETBP1-mutant primary cells and a SETBP1-mutant mouse model.SETBP1D868N-expressing progenitors showed a significant growth advantage and increased self-renewal compared to controls... This study highlights the critical role of SETBP1 mutations in orchestrating transcriptional programs that drive leukemogenesis in myeloid malignancies. Mutant SETBP1 promotes granulocytic progenitor expansion and induces a leukemic transcriptional program. Our findings reveal that SETBP1 interacts with several epigenetic regulators, particularly KAT7, to modulate chromatin."

Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Chronic Neutrophilic Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CD14 • CD34 • HOXA9 • ITGAM • KAT6A • MECOM • MEIS1 • SETBP1

KAT6A and B inhibition increases efficacy of differentiation and GD2 targeting immunotherapy in neuroblastoma (AACR 2025) - "Reflecting the epigenetic reprogramming of these tumor cells, we observed that expression of GD2, a cell surface glycosphingolipid that is a target of antibody-based and CAR T cell therapies in neuroblastoma, was induced on GD2low neuroblastoma cells by treatment with retinoic acid plus PF-9363 both in vitro and in vivo, leading to increased effectiveness of anti-GD2 CAR T cell therapy in neuroblastoma. These studies nominate KAT6A/B inhibition as a novel approach to enhance the effectiveness of differentiation and GD2-immunotherapy in neuroblastoma and may be relevant for other tumors of neuro-ectodermal origin."

Clinical • IO biomarker • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • GATA3 • HOXB6 • KAT6A • MYCN • PHOX2B

Unique breast cancer CDX panels for KAT6, ER, and CDK4/6 (AACR 2025) - "To accelerate the discovery of anti-ER+ breast cancer drugs through KAT6A and CDK4/6 pathways, we generated four specific CDX models which cover the most popular ER+/KAT6A cell lines (BT-474, ZR-75-1) and ER+/ CDK4/6 cell lines (MCF-7, HCC1428) and revealed the efficacy of KAT6A inhibitor (PF-9363), CDK4/6 inhibitor (Palbociclib), or ER inhibitor (Fulvestrant) on these breast CDX models. The in vivo MOA of these inhibitors were also evaluated by Western Blotting and pathological examination."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • KAT6A

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia. (PubMed, bioRxiv) - "Moreover, PF-9363 or genetic depletion of KAT7 can also overcome acquired genetic/non-genetic resistance to Menin inhibition. These data provide the molecular rationale for rapid clinical translation of combination therapy in MLL-FP leukaemia."

Journal • Preclinical • Gene Therapies • Hematological Malignancies • Leukemia • Oncology • KAT6A • KAT6B

Novel combination therapy with a KAT6A/B inhibitor together with retinoids induces irreversible differentiation of neuroblastoma cells (AACR 2024) - "In this screen, we found that an inhibitor of the histone H3K23 acetyltransferases KAT6A/B, PF-9363, synergistically inhibits neuroblastoma cell growth in combination with retinoic acid...Importantly, this combination treatment renders the differentiated cell state irreversible, such that it is maintained after retinoic acid is withdrawn, with continued suppression of the adrenergic CRC and MYCN expression. In conclusion, the retino-sympathetic differentiated cell state induced by retinoic acid in neuroblastoma becomes irreversible when the cells are also treated with an inhibitor of the KAT6A/B histone H3K23 acetyltransferases, implicating the essential role of these enzymes in restoring the proliferative immature progenitor phenotype in adrenergic neuroblastoma cells."

Combination therapy • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • KAT6A • MYCN

HATS off to KAT6A/B inhibitors: A new way to target estrogen-receptor-positive breast cancer. (PubMed, Cell Chem Biol) - "Inhibitors for the KAT6 family of histone acetyltransferases (HATs) have been actively pursued due to the oncogenic roles of KAT6A in human cancer. CTx-648 is a novel KAT6A/B inhibitor with excellent pharmacokinetic properties and in vivo efficacy that represents a promising new treatment strategy for estrogen-receptor-positive breast cancer."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • KAT6A

Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer. (PubMed, Cell Chem Biol) - "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."

Epigenetic controller • Journal • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • KAT6A • KAT6B

[VIRTUAL] First-in-class KAT6A/KAT6B inhibitor CTx-648 (PF-9363) demonstrates potent anti-tumor activity in ER+ breast cancer with KAT6A dysregulation (AACR 2021) - "In vivo target validation studies showed strong anti-tumor activity of CTx-648 in several ER+ breast cancer cell line and patient-derived xenograft models, including models harboring endocrine therapy resistance ESR1 mutations, highlighting promise for this novel therapy in ER+ breast cancer population. Based on the strength of the pre-clinical data, a selective KAT6 inhibitor (PF-07248144) is now commencing a Phase 1 clinical study in Advanced or Metastatic Solid Tumors."

Acute Myelogenous Leukemia • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • ER • KAT8