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Purity: ≥98%
BIX01294 is a novel and potent inhibitor of G9a histone methyltransferase with anticancer activity. It inhibits G9a with an 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. It demostrates excellent antiproliferative activity and high in vivo antitumor efficacy. 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 hours) [1]. Significant increase in MLKL S345 phosphorylation is caused by BIX-01294 (1 μM)[1]. In recurrent tumor cell lines, BIX-01294 (1 μM) strongly upregulates the traditional p53 targets Gadd45a and Cdkn1a (p21)[1]. Both primary and recurrent tumor cells exhibit decreased H3K9me2 levels in response to BIX-01294 (1 μM; 6 days) [1]. Necroptotic cell death in recurring tumor cells is induced by BIX-01294. Necrostatin-1 (30 μM) partially counteracts the 24-hour, 750 nM-induced cell death caused by BIX-01294[1]. In mouse ES cells, BIX-01294 (4.1 μM) resulted in a 20% decrease in unmodified H3K9 fragments in H3K9me2, which was significantly accompanied by an increase. In wild-type ES cells, BIX-01294 significantly lowers H3K9me2, but only slightly lowering H3K9me3 and H3K9me1 [2]. Even at 45 μM, BIX-01294 did not inhibit other histone methyltransferases. SUV39H1 (H320R) and PRMT1[2] are unaffected by BIX-01294 in the measured concentration range (up to 10 μM). G9a and S-adenosylmethionine (SAM) are inhibited by BIX-01294 in a non-competitive way[2]. Reduced BrdU binding is caused by BIX-01294 (1 μg/mL) in fetal PASMC. PASMC migration caused by PDGF[3] was inhibited by BIX-01294 therapy.
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| ln Vivo |
In recurring tumor cells, BIX-01294 (10 mg/kg; i.p.; three times weekly for two weeks) dramatically lowered 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 hrs (hours) 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]. Kubicek S, 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 |
C28H38N6O2
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|---|---|
| Molecular Weight |
490.640326023102
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| CAS # |
935693-62-2
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| Related CAS # |
BIX-01294 trihydrochloride;1392399-03-9
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| SMILES |
N1C2C(=CC(=C(C=2)OC)OC)C(NC2CCN(CC3C=CC=CC=3)CC2)=NC=1N1CCCN(C)CC1
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| Synonyms |
BIX01294 HCl;BIX01294; BIX-01294; BIX 01294;N-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine
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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 | 2.0382 mL | 10.1908 mL | 20.3815 mL | |
| 5 mM | 0.4076 mL | 2.0382 mL | 4.0763 mL | |
| 10 mM | 0.2038 mL | 1.0191 mL | 2.0382 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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