Histone acetyltransferases (HATs) play a vital role in a range of epigenetic pathways by the acetylation of histones using acetyl-CoA as substrate. MYST family is responsible for a wide range of cellular events and comprising approximately one-third in the human genome. WM-119 is a selective inhibitor of KAT6A of MYST[1]. WM119 can bind to KAT6A, KAT5 and KAT7 at a binding KD values of 2 nM, 2.2 μM and 0.5 μM, respectively. In vitro, treatment with WM-1119 resulted in increased levels of Cdkn2a and Cdkn2b mRNA and P16 and P19 proteins, as well as a delayed increase in Cdkn1a mRNA. WM-1119 inhibited the proliferation of B cell lymphoma cell line EMRK1184 with IC50 value of 0.25 μM. Treatment of mouse embryonic fibroblasts (MEFs) with 1 μM WM-1119 induced cell cycle arrest in G1 and a senescence phenotype. In vivo, administered WM-1119 at 50 mg/kg via intraperitoneal injection four times daily for 14 days substantially reduced the level of H3K9ac in lymphoma cells, and the proportion and overall number of lymphoma cells in mice, suggesting that WM-1119 was effective in treating lymphoma in vivo[2].
作用机制
M-1119 competes with acetyl-CoA in the MYST lysine acetyltransferase domain[2].
WM-1119 细胞实验
Cell Line
Concentration
Treated Time
Description
References
PDLSCs
25 µM
24 hours
Inhibition of KAT6A significantly reduced the expression and acetylation level of YAP, thereby affecting the RANKL/OPG ratio in PDLSCs.
Prog Orthod. 2024 Aug 12;25(1):29.
GIST430
1 μM
42 days
Inhibition of MOZ complex, reduced GIST cell proliferation
Cancer Discov. 2022 Jul 6;12(7):1804-1823.
GIST-T1
0.1 μM
5 days
Inhibition of MOZ complex, reduced GIST cell proliferation
Cancer Discov. 2022 Jul 6;12(7):1804-1823.
MOZ-TIF2 LSK cells
3 nM to 10 μM
15 days
To evaluate the effect of WM-1119 on the proliferation of MOZ-TIF2 LSK cells. Results showed a dose-dependent decrease in proliferation with an IC50 of 25 nM.
Proc Natl Acad Sci U S A. 2024 Jun 25;121(26):e2405905121.
MT2 cells
0.1µM and 1µM
Every 2 days
WM-1119 completely abrogated the proliferative and clonogenic potential of MT2 cells
J Hematol Oncol. 2024 Oct 8;17(1):91.
ER-HOXA9 cells
4μM
WM-1119 treatment significantly impaired the clonogenic potential of ER-HOXA9 cells.
Cancer Discov. 2022 Mar 1;12(3):792-811.
RN2 cells
4μM
4 days
WM-1119 treatment significantly increased surface expression of CD11b in RN2 cells, indicating induction of myeloid differentiation.
Cancer Discov. 2022 Mar 1;12(3):792-811.
MOLM-13 cells
4μM
4 days
WM-1119 treatment significantly increased surface expression of CD11b in MOLM-13 cells, indicating induction of myeloid differentiation.
Cancer Discov. 2022 Mar 1;12(3):792-811.
UWB1.289-R cells
25 μm
72 hours
Inhibited the catalytic function of KAT6A but had no effect on PARPi sensitivity
Adv Sci (Weinh). 2024 Sep;11(34):e2400140.
SKOV3-R cells
25 μm
72 hours
Inhibited the catalytic function of KAT6A but had no effect on PARPi sensitivity
Adv Sci (Weinh). 2024 Sep;11(34):e2400140.
WM-1119 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Orthodontic tooth movement model
Periodontal injection
50 µg/kg
Injected at 0, 2, 4, and 6 days, lasting for 7 days
Inhibition of KAT6A significantly reduced the distance of tooth movement, decreased the number of TRAP-positive cells and RANKL-positive cells, and increased the number of OPG-positive cells.
Prog Orthod. 2024 Aug 12;25(1):29.
Nude mice
GIST-T1 cell line xenograft
Oral gavage
50 mg/kg
Three times daily for 28 days
Inhibition of MOZ complex, significantly reduced tumor burden
Cancer Discov. 2022 Jul 6;12(7):1804-1823.
Balb/c nude mice
Subcutaneous xenograft model of SKOV3-R cells
Intraperitoneal injection
60 mg/kg
2-4 times per week for 2-4 weeks
Inhibited the catalytic function of KAT6A but had no effect on PARPi sensitivity
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