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I-BET151

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Chemical Structure| 1300031-49-5 同义名 : GSK1210151A
CAS号 : 1300031-49-5
货号 : A111934
分子式 : C23H21N5O3
纯度 : 98%
分子量 : 415.445
MDL号 : MFCD22124472
存储条件：

粉末 Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(252.74 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • BET

    BRD3, IC50:0.25 μM

    BRD4, IC50:0.5 μM
描述 The Bromodomain and Extra-Terminal Domain BET (Bromodomain and Extra-Terminal Domain) family is characterized by the presence of two tandem bromodomains and an extra-terminal domain. BET proteins can govern the assembly of histone acetylation-dependent chromatin complexes, thus regulating gene expression. I-BET-151 is a potent BET protein inhibitor with IC50 values of 0.5, 0.25 and 0.79 μM for BRD2, BRD3 and BRD4 (measure by FP ligand displacement assay), respectively. I-BET-151 shows more potential and selective effect on growth inhibition of MLL-fusion leukemic cell lines with IC50 values of 15 - 192 nM for MV4-11, RS4-11, MOLM13 and NOMO1 cell lines. Treatment with I-BET-151 for 72h cause a marked induction of apoptosis and a prominent G0/G1 arrest in MOLM13 and MV4-11 cells. This may due to the ability of I-BET-151 to inhibit the transcription of MLL targeted gene such as BCL2, CDK6 or MYC, which regulated by aberrantly co-opted SEC and PAFc in MLL fusions. Treatment with I-BET-151 at dose of 30mg/kg, i.p., daily, for 21 days can provide excellent control of MLL leukemia progression in xenotransplanted model of disseminated human MLL–AF4 leukemia and syngeneic model of murine MLL–AF9 leukemia. Compared with I-BET-762 or JQ1, I-BET-151 showed enhanced in vivo pharmacokinetics and terminal half-life to enable prolonged in vivo studies[1]. I-BET151 has anti-tumor activity in hematological malignancies, including myeloma[2], acute myeloid leukemia[3], lymphoma[4] and myeloproliferative neoplasms[5]. Similar with I-BET-762, I-BET-151 can effectively inhibit IL-6 production in LPS-stimulated PMBCs[6], as well as osteoclast genesis and inflammatory bone resorption[7].
作用机制 I-BET-151 can bind to the acetylated-lysine (AcK) recognition pocket of the BET protein and inhibit the transcription activity of key gene through the displacement of BRD3/4, PAFc and SEC components from chromatin[1].
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
A172 ~10 μM Function assay reduces cellular ATP with IC50 of 1.28 μM 24496381
A2 ~10 μM Function assay reactivates latent HIV-1 23255218
A72 ~10 μM Function assay reactivates latent HIV-1 23255218
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.41mL

0.48mL

0.24mL

12.04mL

2.41mL

1.20mL

24.07mL

4.81mL

2.41mL
参考文献

[1]Dawson MA, Prinjha RK, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011 Oct 2;478(7370):529-33.

[2]Chaidos A, Caputo V, et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood. 2014 Jan 30;123(5):697-705.

[3]Dawson MA, Gudgin EJ, et al. Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia. Leukemia. 2014 Feb;28(2):311-20.

[4]Tolani B, Gopalakrishnan R, et al. Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors. Oncogene. 2014 May 29;33(22):2928-37.

[5]Wyspiańska BS, Bannister AJ, et al. BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms. Leukemia. 2014 Jan;28(1):88-97.

[6]Seal J, Lamotte Y, et al. Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A). Bioorg Med Chem Lett. 2012 Apr 15;22(8):2968-72.

[7]Park-Min KH, Lim E, et al. Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation. Nat Commun. 2014 Nov 13;5:5418.

[8]Piquereau J, Boet A, et al. The BET Bromodomain Inhibitor I-BET-151 Induces Structural and Functional Alterations of the Heart Mitochondria in Healthy Male Mice and Rats. Int J Mol Sci. 2019 Mar 27;20(7). pii: E1527.