生物活性

• 靶点

  Bromodomain 2 IC50:0.5μM

  Bromodomain 3 IC50:0.25μM

  Bromodomain 4 IC50:0.79μM

• 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
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  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

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• 动物研究
  剂量	Rat[8] (p.o.): 2 mg/kg, 10 mg/kg, mice[8] (p.o.): 50 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Mice[1] Rats[1] Dogs[1] Dose i.v. p.o. i.v. p.o. i.v. p.o. Administration 3 mg/kg 3 mg/kg 1 mg/kg 2 mg/kg 1 mg/kg 3 mg/kg Cmax 3.87 ± 1.03 μM (p.o.) 0.72 ± 0.24 μM (p.o.) 0.09 ± <0.1 μM (p.o.) T1/2 1.8 ± 0.3 h (i.v.) 2.6 ± 0.3 h (p.o.) 1.7 ± 0.3 h (i.v.) 2.1 ± 0.3 h (p.o.) 1.2 ± 0.1 h (i.v.) 4.7 h, 2.2 h (p.o.) F 1 66 ± 26% 16 ± 3% AUClast 15.0 ± 1.5 μM/h (i.v.) 18.2 ± 4.9 μM/h (p.o.) 2.3 ± 0.5 μM/h (i.v.) 2.8 ± 1.1 μM/h (p.o.) 1.1 ± 0.3 μM/h (i.v.) 0.5 ± 0.2 μM/h (p.o.) Tmax 1.02 h (p.o.) 0.75 h (p.o.) 2 h (p.o.) Vss 1.2 ± 0.1 l/kg (i.v.) 2.1 ± 0.1 l/kg (i.v.) 3.0 ± 0.6 l/kg (i.v.) AUC∞ 15.3 ± 2.3 μM/h (i.v.) 19.1 ± 4.8 μM/h (p.o.) 2.4 ± 0.6 μM/h (i.v.) 2.9 ± 1.2 μM/h (p.o.) 1.2 ± 0.3 μM/h (i.v.) 0.8, 0.3 μM/h (p.o.) CL 8 ± 1 ml/min/kg (i.v.) 18 ± 5 ml/min/kg (i.v.) 38 ± 10 ml/min/kg (i.v.) MRT 2.5 ± 0.2 h (i.v.) 2.1 ± 0.5 h (i.v.) 1.3 ± 0.1 h (i.v.)

• 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.

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