GW841819X

GW841819X is an analogue of (+)-JQ1 and a novel inhibitor of BET bromodomains. GW841819X was a single enantiomer but of undefined chirality at the 4-position of the benzodiazepine ring ³.

GW841819X and JQ1 were recently discovered that bind to the acetyl-lysine binding pocket of BET bromodomains with Kd ranges from 50 to 370 nM [1]. GW841819X bounded to both the individual BD1 and BD2 domains with affinities of 46 and 52.5 nM, respectively. GW841819X-Brd3 interaction was estimated to be around 70 nM ⁴.

GW841819X displayed activity in vivo against NUT-midline carcinoma, multiple myeloma, mixed-lineage leukemia, and acute myeloid leukemia ¹. It also potent induced the ApoA1 reporter gene with an EC50 of 440 nM. It had very little effect on LDL-R luciferase activity at the concentrations at which it induces ApoA1 expression, suggesting that the effect is indeed specific ³. GW841819X competed directly with GATA1 site for BD1 binding and also specifically blocked the interaction between Brd3 and acetylated GATA1 ⁴. Recent findings reported that GW841819X are chose as an interest compound to further develop into potential drugs against diseases including cancer, HIV infection and heart disease ².

References:
1. Baud MG, Lin-Shiao E, Cardote T et al. Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes. Science. 2014 Oct 31;346(6209):638-41.
2. Floyd SR, Pacold ME, Huang Q et al. The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature. 2013 Jun 13;498(7453):246-50.
3. Chung CW, Coste H, White JH et al. Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J Med Chem. 2011 Jun 9;54(11):3827-38.
4. Gamsjaeger R, Webb SR, Lamonica JM et al. Structural basis and specificity of acetylated transcription factor GATA1 recognition by BET family bromodomain protein Brd3. Mol Cell Biol. 2011 Jul;31(13):2632-40.