BIX-01294 (trihydrochloride)

BIX-01294 trihydrochloride is a reversible and highly selective G9a and GLP Histone Methyltransferase inhibitor, with IC₅₀s of of 1.7 μM and 0.9 μM, respectively. BIX-01294 trihydrochloride inhibits G9a/GLP by competing for binding with the amino acids N-terminal of the substrate lysine residue. BIX-01294 trihydrochloride, a (1H-1,4-diazepin-1-yl)-quinazolin-4-yl amine derivative, induces necroptosis and autophagy. BIX-01294 trihydrochloride has antitumor activity in recurrent tumor cells^{[1][2][3][4][5]}. IC50 & Target: IC50: 2.7 μM (G9a in DELFIA assay)^[2]
IC50: 1.9 μM for G9a and 0.7 μM for GLP^[5] In Vitro: BIX-01294 (2 μM; 48 h) trihydrochloride selectively inhibits recurrent tumor cell growth^[1].
BIX-01294 (1 μM) trihydrochloride leads to a marked increase in phosphorylation of S345 of MLKL^[1].
BIX-01294 (1 μM) trihydrochloride significantly upregulates the canonical p53 targets Cdkn1a (p21) and Gadd45a in recurrent tumor cell lines^[1].
BIX-01294 (1 μM; 6 days) trihydrochloride causes the reduction in H3K9me2 levels in primary and recurrent tumor cells^[1].
BIX-01294 trihydrochloride leads to necroptotic cell death in recurrent tumor cells. Necrostatin-1 (30 μM) partially reverses cell death induced by BIX-01294 (750 nM; 24 h) trihydrochloride^[1].
BIX-01294 (4.1 μM; for 2 days) trihydrochloride causes around a 20% reduction, concomitant with a comparable increase in the unmodified H3K9 fragment in H3K9me2 in mouse ES cells. BIX-01294 trihydrochloride causes pronounced reduction in H3K9me2 and a small decrease for H3K9me3 and H3K9me1 in wild-type ES cells^[2].
BIX-01294 trihydrochloride has no inhibition of the other histone methyltransferases even at concentrations of 45 μM. BIX-01294 trihydrochloride does not affect SUV39H1 (H320R) and PRMT1 within the tested concentration range (up to 10 μM)^[2].
BIX-01294 trihydrochloride inhibits G9a in an uncompetitive manner with S-adenosyl-methionine (SAM)^[2].
BIX-01294 (1 µg/mL) causes reduction in the BrdU incorporation of fetal PASMCs. BIX-01294 treatment decreases the PASMCs migration induced by PDGF^[3].
In Vivo: BIX-01294 trihydrochloride (10 mg/kg; IP; three times a week for 2 weeks) significantly reduces tumor growth and tumor burden in recurrent tumor cells. Primary tumor growth is not inhibited^[1].