1403764-72-6|PFI-1|CsnPharm

CAS No.: 1403764-72-6

PFI-1 Catalog No. CSN17164

Synonyms: PF-06405761;PF-6405761

PFI-1 is a highly selective BET (bromodomain-containing protein) inhibitor for BRD4 with IC50 of 0.22 μM and for BRD2 with IC50 of 98 nM in a cell-free assay.

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实验方案

技术信息

生物活性

描述PFI-1 is a potent and selective BET inhibitor with IC50 value of 0.22μM for BRD4(1). PFI-1 exhibited inhibitory effect on IL6 production from human blood mononuclear cells stimulated by LPS with EC50 value of 1.89μM^[3]. PFI-1 has antiproliferative effects on leukemic cell lines and efficiently abrogates their clonogenic growth with GI50 values ranging in 0.8-11μM. Exposure of sensitive cell lines with PFI-1 resulted in G1 cell cycle arrest, downregulation of MYC expression in MV4;11 cells, as well as induction of apoptosis and induced differentiation of primary leukemic blasts. Cells exposed to PFI-1 showed significant downregulation of Aurora B kinase, thus attenuating phosphorylation of the Aurora substrate H3S10^[4].
作用机制PFI-1 could bind to BET protein through the key interaction with Asn140. And the urea carbonyl also makes a water-bridged hydrogenbond interaction with the phenolic OH of Tyr97^[3]. PFI-1 efficiently blocks the interaction of BET BRDs with acetylated histone tails. It acts as an acetyl-lysine (Kac) mimetic inhibitor efficiently occupying the Kac binding site in BRD4 and BRD2.^[4]

动物研究

剂量

Rat: 1 mg/kg^[1] (i.v.); 2 mg/kg^[1] (p.o.) Mice: 2 mg/kg^[1] (s.c.)

给药途径

i.v., p.o.

动物药代数据

Animal	Mice^[1]	Rats^[1]
Dose	2 mg/kg	1 mg/kg (i.v.) 2 mg/kg (p.o.)
Administration	s.c.	i.v. p.o.
F		32% (p.o.)
V_d		1 L/kg (i.v.)
T_1/2	2 h	1 h (i.v.)
T_max	1 h
CL		18 ml/min/kg (i.v.)
C_max	58 ng/ml

参考文献

[1] Fish PV, Filippakopoulos P, et al. Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit. J Med Chem. 2012 Nov 26;55(22):9831-7.
[2] Picaud S, Da Costa D, et al. PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains. Cancer Res. 2013 Jun 1;73(11):3336-46.
[3] Fish PV, Filippakopoulos P, Bish G, Brennan PE, Bunnage ME, Cook AS, Federov O, Gerstenberger BS, Jones H, Knapp S, Marsden B, Nocka K, Owen DR, Philpott M, Picaud S, Primiano MJ, Ralph MJ, Sciammetta N, Trzupek JD. Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit. J Med Chem. 2012 Nov 26;55(22):9831-7. doi: 10.1021/jm3010515. Epub 2012 Nov 8. PMID: 23095041; PMCID: PMC3506127.
[4] Picaud S, Da Costa D, Thanasopoulou A, Filippakopoulos P, Fish PV, Philpott M, Fedorov O, Brennan P, Bunnage ME, Owen DR, Bradner JE, Taniere P, O'Sullivan B, Müller S, Schwaller J, Stankovic T, Knapp S. PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains. Cancer Res. 2013 Jun 1;73(11):3336-46. doi: 10.1158/0008-5472.CAN-12-3292. Epub 2013 Apr 10. PMID: 23576556; PMCID: PMC3673830.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.8786 mL
- 14.3931 mL
- 28.7862 mL
- 5 mM
- 0.5757 mL
- 2.8786 mL
- 5.7572 mL
- 10 mM
- 0.2879 mL
- 1.4393 mL
- 2.8786 mL

技术信息

CAS号

1403764-72-6

储存条件

粉末: Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C16H17N3O4S

运输

蓝冰

分子量

347.39

别名

PF-06405761;PF-6405761

溶解度

DMSO	insoluble
Water	insoluble

动物实验配方

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