KAT6, a histone acetyltransferase from the MYST family, has emerged as an attractive oncology target due to its role in regulating genes that control cell cycle progression and cellular senescence. Amplification of the KAT6A gene has been seen among patients with worse clinical outcome in ER breast cancers. Although multiple inhibitors have been reported, no KAT6 inhibitors have been approved to date. Here, we report the fragment-based discovery of a series of N-(1-phenyl-1H-1,2,3-triazol-4-yl)benzenesulfonamide KAT6 inhibitors and early hit-to-lead efforts to improve the KAT6 potency.
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| http://dx.doi.org/10.1016/j.bmcl.2024.129948 | DOI Listing |
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Understanding the molecular pathogenesis of MLL fusion oncoprotein (MLL-FP) leukaemia has spawned epigenetic therapies that have improved clinical outcomes in this often-incurable disease. Using genetic and pharmacological approaches, we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in MLL-FP leukaemia. Whilst inhibition of KAT6A/B is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, increases the therapeutic efficacy.
View Article and Find Full Text PDFThe small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency.
J Hematol Oncol
October 2024
Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.
Article Synopsis
- Researchers studied two proteins, KAT6A and KMT2A, that can cause leukemia when changed or damaged.
- They tested a new medicine, WM-1119, which stops KAT6A from working to see if it could help fight a kind of leukemia.
- The results showed that WM-1119 was very effective at stopping cancer cells from growing and helped the cells become more like normal blood cells.
Identification of triazolyl KAT6 inhibitors via a templated fragment approach.
Bioorg Med Chem Lett
November 2024
Prelude Therapeutics Incorporated, 175 Innovation Boulevard, Wilmington, DE 19805, USA. Electronic address:
KAT6, a histone acetyltransferase from the MYST family, has emerged as an attractive oncology target due to its role in regulating genes that control cell cycle progression and cellular senescence. Amplification of the KAT6A gene has been seen among patients with worse clinical outcome in ER breast cancers. Although multiple inhibitors have been reported, no KAT6 inhibitors have been approved to date.
View Article and Find Full Text PDFA MOZ-TIF2 leukemia mouse model displays KAT6-dependent H3K23 propionylation and overexpression of a set of active developmental genes.
Proc Natl Acad Sci U S A
June 2024
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115.
Aberrant regulation of chromatin modifiers is a common occurrence across many cancer types, and a key priority is to determine how specific alterations of these proteins, often enzymes, can be targeted therapeutically. MOZ, a histone acyltransferase, is recurrently fused to coactivators CBP, p300, and TIF2 in cases of acute myeloid leukemia (AML). Using either pharmacological inhibition or targeted protein degradation in a mouse model for MOZ-TIF2-driven leukemia, we show that KAT6 (MOZ/MORF) enzymatic activity and the MOZ-TIF2 protein are necessary for indefinite proliferation in cell culture.
View Article and Find Full Text PDFInhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER human epidermal growth factor receptor-negative (HER2) metastatic breast cancer (mBC).
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