PRMT5 is a protein arginine methyltransferase that catalyzes H4R3me2 and H3R8me2. It is active on non-histone substrates, such as p53 and programmed cell death 4, and acts as a transcriptional repressor. GSK3326595 is a potent, selective inhibitor of PRMT5 with an IC50 value of 6.2 ± 0.8 nM[1]. It inhibited tumor growth both in vitro and in animal models[2]. Treatment with GSK3326595 (40 mg/kg from day 10) plus anti-PD1 antibodies (200 μg/mouse at days, 8, 11, 14, 17 and 20) augmented the anti-tumor response, reflected in reduced tumor size in both B16 (Fig. 8E; fig. S10C and S10D) and YUMM1.7 melanoma models[3].
GSK3326595 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Z-138 cells
200 nM
3 days
Evaluate cell cycle distribution
Sci Rep. 2018 Jun 26;8(1):9711.
A375 cells
500 nM
6 days
Enhance the efficacy of palbociclib
Proc Natl Acad Sci U S A. 2019 Sep 3;116(36):17990-18000.
HT144 cells
250 nM
6 days
Enhance the efficacy of palbociclib
Proc Natl Acad Sci U S A. 2019 Sep 3;116(36):17990-18000.
GSK3326595 pre-treatment primed peritoneal macrophages to obtain a pro-inflammatory phenotype upon IFN-γ stimulation, evidenced by increased iNOS and IP-10 expression levels.
J Cell Mol Med. 2023 Apr;27(8):1056-1068.
HEK-293T cells
100 nM
48 hours
GSK3326595 dramatically decreased interaction between ACE2 and the RBD
J Med Virol. 2023 Jan;95(1):e28158.
MC38/gp100 and B16 tumor cells
40 nM to 10 µM
5 days
Inhibits tumor cell growth
J Immunother Cancer. 2024 Sep 23;12(9):e009600.
HT-29 cells
1 µM
5 days
To evaluate the effect of MTDIA and AG-270 on HT-29 cell growth, the results showed that the combination of MTDIA and AG-270 significantly inhibited cell growth and induced apoptosis.
J Biol Chem. 2024 Jan;300(1):105492.
A375AR cells
500 nM
6 days
Inhibit PRMT5 activity, restore sensitivity to palbociclib
Proc Natl Acad Sci U S A. 2019 Sep 3;116(36):17990-18000.
HT144AR cells
250 nM
6 days
Inhibit PRMT5 activity, restore sensitivity to palbociclib
Proc Natl Acad Sci U S A. 2019 Sep 3;116(36):17990-18000.
CAL-1 cells
0.001, 0.005, 0.02, 0.08, 0.31, 1.25, 5 µM
72 hours
To evaluate the effect of GSK3326595 on the growth of CAL-1 cells, the results showed that GSK3326595 significantly inhibited the growth of CAL-1 cells and induced apoptosis.
Blood Adv. 2022 Sep 27;6(18):5330-5344.
Pancreatic cancer cells
20 µM
72 hours
GSK3326595 inhibits PRMT5 activity, re-activates the dysregulated Hippo signaling pathway, and inhibits the growth of pancreatic cancer cells.
EMBO J. 2023 Dec 1;42(23):e114558.
GSK3326595 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Z-138 xenograft model
Oral
100 mg/kg
Twice daily for 21 days
Assess the anti-tumour activity of GSK3326595
Sci Rep. 2018 Jun 26;8(1):9711.
NOD/SCID mice
NOD/SCID mice
Oral
100 mg/kg
Once daily for 20 days
To evaluate the effect of GSK3326595 on tumor growth in NOD/SCID mice, the results showed that GSK3326595 significantly inhibited tumor growth and induced apoptosis in normal gut cells.
J Biol Chem. 2024 Jan;300(1):105492.
BALB/c Nude mice
A375 tumor xenograft model
Oral
100 mg/kg
Daily until tumor progression
Delay the emergence of palbociclib resistance, enhance therapeutic efficacy
Proc Natl Acad Sci U S A. 2019 Sep 3;116(36):17990-18000.
Immunodeficient mice
Pancreatic cancer xenograft model
Intravenous injection
100 mg/kg
Every 3 days for 30 days
GSK3326595 significantly impeded the progression of pancreatic cancer, re-activated the Hippo signaling pathway, and inhibited tumor growth.
EMBO J. 2023 Dec 1;42(23):e114558.
NSG mice
CAL-1 xenograft model
Oral
150 mg/kg
Twice daily until humane endpoint
To evaluate the effect of GSK3326595 on tumor growth in the CAL-1 xenograft model, the results showed that GSK3326595 significantly inhibited tumor growth and reduced SDMA-modified protein levels.
Blood Adv. 2022 Sep 27;6(18):5330-5344.
C57BL/6 mice
MC38/gp100 Mtap-KO or B16 Mtap-KO tumor models
Oral
30 mg/kg/day
Once per day for the duration of the study
Superior antitumor activity in combination with anti-PD-1
J Immunother Cancer. 2024 Sep 23;12(9):e009600.
Mice
B16 and YUMM1.7 melanoma models
Oral
40 mg/kg
QD, from day 10
Combination of GSK3326595 with anti-PD1 antibody therapy enhanced the anti-tumor response, reflected in reduced tumor size.
Sci Transl Med. 2020 Jul 8;12(551):eaaz5683
Mice
LDL receptor knockout mice
Intraperitoneal injection
5 mg/kg
3 times per week for 9 weeks
Chronic GSK3326595 treatment did not alter the inflammatory state or atherosclerosis susceptibility in mice, but significantly increased hepatic triglyceride levels.
J Cell Mol Med. 2023 Apr;27(8):1056-1068.
MYC-ON mice
HCC xenograft models
50 mg/kg/day
Significantly suppressed tumor growth compared with anti–PD-1 monotherapy
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