The histone acetyltransferase p300/CBP is a transcriptional coactivator involved in many regulatory pathways during tumorigenesis. C646 is a selective and competitive p300 inhibitor with a Ki value of 400nM. Treatment of C3H 10T1/2 mouse fibroblasts with C646 (25μM) resulted in a reduction in the levels of histone H3 and H4 acetylation. C646 at a concentration of 25μM also inhibited TSA-induced acetylation in mouse fibroblasts. C646 at 10μM was capable of reducing 3H-thymidine incorporation in several human cancer cell lines. The IC50 value of C646 for the growth of melanoma cell line WM983A was 10-20μM[3] The suppression of P300 by C646 via intraperitoneal injection (30nmol/g/day for two weeks) reduced the level of blood glucose, rescued impaired autophagic flux, and resulted in an 18.5% increase in muscle mass in db/db mice.[4]
作用机制
C646 is a competitive, highly selective inhibitor of p300 versus other acetyltransferases.[3]
C646 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Porcine aortic valve interstitial cells (pAVICs)
10 μM
3 days
C646 treatment significantly reduced calcium deposition, decreased ALP activity, and reduced the expression of osteogenic marker genes, indicating that C646 can attenuate high-calcium/high-phosphate-induced calcification.
Exp Mol Med. 2019 Jul 10;51(7):1-14.
Adult mouse primary cardiac fibroblasts (ACFs)
3 μM
24 h
Inhibit the acetyltransferase activity of P300 and observe the effect of C646 on fibroblast activation. Results showed that C646 pretreatment reversed CAR3 deficiency-induced suppression of fibroblast activation and improved cardiac healing and collagen synthesis.
Int J Biol Sci. 2024 Feb 25;20(5):1796-1814.
Drosophila S2 cells
30 μM
10 min
CBP inhibition resulted in down-regulation of 3790 genes, indicating the critical role of CBP in transcription regulation
Mol Cell. 2017 Nov 2;68(3):491-503.e5.
HCT116 colon cancer cells
10 µM
12 and 96 h
To assess the effects of C646 on the transcriptome of HCT116 cells, it was found that C646 downregulated genes related to the WNT signaling pathway.
Epigenetics Chromatin. 2015 Feb 24;8:9.
PANC1 pancreatic cancer cells
10 µM
12 and 96 h
To assess the effects of C646 on the transcriptome of PANC1 cells, it was found that C646 downregulated cell cycle-related genes but did not significantly affect the WNT signaling pathway.
Epigenetics Chromatin. 2015 Feb 24;8:9.
SK-BR-3
8 μM
72 h
C646 prevented PEPD KD from causing K373 acetylation of p53 mutants and induction of p53 target proteins, despite profound PEPD KD.
Commun Biol. 2021 Dec 8;4(1):1373.
MDA-MB-231
8 μM
72 h
C646 prevented PEPD KD from causing K373 acetylation of p53 mutants and induction of p53 target proteins, despite profound PEPD KD.
Commun Biol. 2021 Dec 8;4(1):1373.
C646 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 male mice
Colon cancer transplantation tumor model
Intraperitoneal injection
30 nmol/g
Every 3 days for 2 weeks
C646 significantly inhibited the growth of CXCL1-overexpressing colon cancer tumors.
Biol Direct. 2022 Nov 25;17(1):34
Mice
MCA205 fibrosarcoma model
Intraperitoneal injection
10 mg/kg
Daily, throughout the treatment
To evaluate the antitumor effects of C646 in vivo, results showed that C646 could enhance the antitumor effects of chemotherapy by inducing autophagy.
Cancer Cell. 2016 Jul 11;30(1):147-160
Mice
Adenine and vitamin D-induced aortic valve calcification model
Subcutaneous injection
1 mg/kg
Once daily for 14 days
C646 treatment significantly attenuated aortic valve calcification and restored the levels of acetylated histones 3 and 4, indicating that C646 has an inhibitory effect on calcification in vivo.
Exp Mol Med. 2019 Jul 10;51(7):1-14.
Mice
Myocardial infarction model
Intraperitoneal injection
15 mg/kg
Once daily for 14 consecutive days
Inhibit the acetyltransferase activity of p300 and observe the effect of C646 on cardiac healing and function. Results showed that C646 pretreatment reversed CAR3 deficiency-induced impairment of cardiac healing and function, and improved collagen synthesis.
Int J Biol Sci. 2024 Feb 25;20(5):1796-1814.
Mice
TC1 and AE17 tumor models
Subcutaneous injection
8.9 mg/kg
Once daily for 3 days
To evaluate the effect of p300i on tumor growth, results showed that p300i significantly inhibited tumor growth.
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