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Purity: ≥98%
BIX01294 triHCl (the tri-hydrochloride salt of BIX01294) is a novel and potent inhibitor of G9a histone methyltransferase with IC50 of 2.7 μM in a cell-free assay. BIX-01294 was discovered by screening a library of 125,000 synthetic and preselected compounds against G9a. BIX-01294 is selective for G9a and GLP (G9a-like protein) over several H3K9 PKMTs including SUV39H1 and ESET, other KMTs such as SET7/9, and the arginine methyltransferase PRTM1. The X-ray crystal structure of GLP and BIX-01294 confirmed that BIX-01294 bound to the histone peptide binding pocket but failed to interact with the lysine binding channel.
| ln Vitro |
Recurrent tumor cell proliferation is selectively inhibited by BIX-01294 (2 μM; 48 h) trihydrochloride[1]. The phosphorylation of MLKL's S345 is markedly increased by BIX-01294 trihydrochloride (1 μM)[1]. In recurrent tumor cell lines, BIX-01294 (1 μM) trihydrochloride strongly upregulates the classical p53 targets Cdkn1a (p21) and Gadd45a[1]. Primary and recurrent tumor cells exhibit a decrease in H3K9me2 levels upon exposure to BIX-01294 (1 μM; 6 days) trihydrochloride[1]. In recurring tumor cells, BIX-01294 trihydrochloride causes necroptotic cell death. A partial reversal of cell death caused by BIX-01294 (750 nM; 24 h) trihydrochloride is achieved using necrostatin-1 (30 μM). In mouse ES cells, BIX-01294 (4.1 μM) trihydrochloride results in approximately a 20% drop and a similar increase in the unmodified H3K9 fragment in H3K9me2. In wild-type ES cells, BIX-01294 trihydrochloride significantly lowers H3K9me2, but H3K9me3 and H3K9me1 only slightly decrease[2]. Even at 45 μM doses, BIX-01294 trihydrochloride does not block any other histone methyltransferases. SUV39H1 (H320R) and PRMT1 are unaffected by BIX-01294 trihydrochloride in the investigated concentration range (up to 10 μM)[2]. In an uncompetitive way, BIX-01294 trihydrochloride inhibits G9a in conjunction with S-adenosyl-methionine (SAM)[2]. In fetal PASMCs, BIX-01294 (1 µg/mL) reduces the amount of BrdU incorporated. Treatment with BIX-01294 reduces the migration of PASMCs brought on by PDGF[3].
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| ln Vivo |
In recurrent tumor cells, BIX-01294 trihydrochloride (10 mg/kg; IP; three times a week for two weeks) dramatically lowers tumor development and tumor burden. Growth of primary tumors is not inhibited[1].
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: Primary or recurrent tumor cells Tested Concentrations: 2 μM Incubation Duration: 48 h Experimental Results: Selectively inhibited recurrent tumor cell growth. |
| Animal Protocol |
Animal/Disease Models: Female MMTV-rtTA; TetO-Her2/neu (MTB;TAN) and TetO-Her2/neu (TAN) mice with recurrent or primary tumor cells[1]
Doses: 10 mg/kg Route of Administration: IP; three times a week for 2 weeks Experimental Results: Dramatically decreased tumor growth and tumor burden in recurrent tumor cells. Primary tumor growth was not inhibited. Slowed the growth of orthotopic recurrent tumors in athymic nude recipients. |
| References |
[1]. Nathaniel W Mabe, et al. G9a Promotes Breast Cancer Recurrence through Repression of a Pro-inflammatory Program. Cell Rep. 2020 Nov 3;33(5):108341.
[2]. Stefan Kubicek, et al. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell. 2007 Feb 9;25(3):473-81. [3]. Yang Q, et al. BIX-01294 treatment blocks cell proliferation, migration and contractility in ovine foetal pulmonary arterial smooth muscle cells. Cell Prolif. 2012 Aug;45(4):335-44. [4]. Iwona Anna Ciechomska, et al. BIX01294, an inhibitor of histone methyltransferase, induces autophagy-dependent differentiation of glioma stem-like cells. Sci Rep [5]. Yanqi Chang, et al.Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat Struct Mol Biol. 2009 Mar;16(3):312-7. |
| Molecular Formula |
C28H41CL3N6O2
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|---|---|
| Molecular Weight |
600.0231
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| CAS # |
1392399-03-9
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| Related CAS # |
BIX-01294;935693-62-2
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| SMILES |
Cl[H].Cl[H].Cl[H].O(C([H])([H])[H])C1=C(C([H])=C2C(=C1[H])C(=NC(=N2)N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])C1([H])[H])N([H])C1([H])C([H])([H])C([H])([H])N(C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])C([H])([H])C1([H])[H])OC([H])([H])[H]
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| Synonyms |
BIX01294; BIX-01294; BIX 01294;N-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-aminetrihydrochloride
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6666 mL | 8.3331 mL | 16.6661 mL | |
| 5 mM | 0.3333 mL | 1.6666 mL | 3.3332 mL | |
| 10 mM | 0.1667 mL | 0.8333 mL | 1.6666 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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