Methionine adenosyltransferases (MATs) are essential enzymes for life as they produce S-adenosylmethionine (SAMe), the biological methyl donor required for a plethora of reactions within the cell[1].
S-adenosylmethionine (SAM) is a central metabolite since it is used as a methyl group donor in many different biochemical reactions[2]. Induction of MAT2A/MAT2B confers growth and survival advantage to cancerous cells, enhancing tumor migration[3]. FIDAS-5 is a potent and orally active methionine S-adenosyltransferase 2A (MAT2A) inhibitor with an IC50 of 2.1 μM. It effectively competes against S-adenosylmethionine (SAM) for MAT2A binding. FIDAS-5 shows anticancer activities. It induces the expression of p21WAF1/CIP1, a cell cycle inhibitor， after 36-hour treatment at 3 μM with both reduced level of SAM and SAH observed in LS174T cells. 7-day treatment with FIDAS-5 at 3 μM significantly inhibits the proliferation of LS174T cells, accompanied with reduced expression of c-Myc and cyclinD1. The liver SAM levels are significantly reduced in mice treated with FIDAS-5 at dose of 20 mg/kg for 1 week. Treatment with FIDAS-5 at 20 mg/kg, p.o., daily, for 2 weeks, significantly inhibits the growth of xenograft tumors of athymic nude mice, without obvious difference in body weight[4].
FIDAS-5 细胞实验
Cell Line
Concentration
Treated Time
Description
References
U251-MG cells
10 μM
10 days
To evaluate the effect of FIDAS-5 on tumorsphere formation, results showed that FIDAS-5 significantly reduced the number and diameter of tumorspheres and decreased the expression levels of SOX2 and OCT4.
Life Med. 2023 Nov 23;2(6):lnad048
U87-MG cells
10 μM
10 days
To evaluate the effect of FIDAS-5 on tumorsphere formation, results showed that FIDAS-5 significantly reduced the number and diameter of tumorspheres and decreased the expression levels of SOX2 and OCT4.
Life Med. 2023 Nov 23;2(6):lnad048
OPM2 cells
250 nM
4 days
Inhibited cell proliferation, reduced BrdU incorporation, and caused G0/G1 and G2 phase cell cycle arrest
Haematologica. 2024 Jan 1;109(1):256-271
JJN3 cells
250 nM
4 days
Inhibited cell proliferation, reduced BrdU incorporation, and caused G0/G1 and G2 phase cell cycle arrest
Haematologica. 2024 Jan 1;109(1):256-271
Hep3B cells
1 μM
72 hours
Induced cell cycle arrest and DNA damage, leading to cellular senescence
Nat Cancer. 2024 Jan;5(1):131-146
Huh7 cells
5 μM
72 hours
Induced cell cycle arrest and DNA damage, leading to cellular senescence
Nat Cancer. 2024 Jan;5(1):131-146
mouse HL-1 cardiomyocytes
5 μM
24-30 hours
Inhibited MAT2A activity, significantly suppressing ferroptosis induced by cystine deprivation
Nat Commun. 2024 Oct 17;15(1):8971
human OS-RC-2 renal carcinoma cells
5 μM
14-18 hours
Inhibited MAT2A activity, significantly suppressing ferroptosis induced by cystine deprivation
Nat Commun. 2024 Oct 17;15(1):8971
human HT1080 fibrosarcoma cells
5 μM
10-14 hours
Inhibited MAT2A activity, significantly suppressing ferroptosis induced by cystine deprivation
Nat Commun. 2024 Oct 17;15(1):8971
mouse embryonic fibroblast (MEF) cells
5 μM
8-12 hours
Inhibited MAT2A activity, significantly suppressing ferroptosis induced by cystine deprivation or blockage of cystine uptake
Nat Commun. 2024 Oct 17;15(1):8971
FIDAS-5 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/KaLwRij mice
5TGM1 model
Intraperitoneal injection
20 mg/kg
Three times a week for 28 days
Significantly reduced tumor burden, decreased percentage of eGFP-positive cells and bone marrow plasmacytosis
Haematologica. 2024 Jan 1;109(1):256-271
Nude mice
Huh7 and Hep3B xenograft models
Intraperitoneal injection
10 mg/kg
Once daily for 7 days
Inhibited tumor growth and induced tumor cell senescence
To evaluate the effect of FIDAS-5 on tumor growth, results showed that FIDAS-5 significantly inhibited the growth of xenografts and conferred a significant survival benefit relative to the vehicle control.
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