GSK778

Product NameGSK778
CAS2451862-42-1
MFC30H33N5O3
MW511.61
EINECS
MOL File2451862-42-1.mol

Chemical Properties

Boiling point	679.6±55.0 °C(Predicted)
Density	1.31±0.1 g/cm3(Predicted)
storage temp.	Store at -20°C
solubility	DMSO : 41.67 mg/mL (81.45 mM; Need ultrasonic)
pka	9.90±0.10(Predicted)
form	Solid
color	White to light yellow
InChIKey	ZORLJXWXFABTPZ-CTNGQTDRSA-N
SMILES	N1C2C(=CC(OC[C@H]3CCNC3)=C(C3=C(C)ON=C3C)C=2)C2N([C@@H](C3=CC=CC=C3)C)C(COC)=NC=2C=1

Usage And Synthesis

Uses

GSK778 (iBET-BD1) is a potent and selective BD1 bromodomain inhibitor of the BET proteins, with IC50s of 75 nM (BRD2 BD1), 41 nM (BRD3 BD1), 41 nM (BRD4 BD1), and 143 nM (BRDT BD1), respectively. GSK778 phenocopies the effects of pan-BET inhibitors in cancer models[1].

in vivo

GSK778 (15mg/kg/BID; i.p. for 30 days) offers a superior survival advantage to iBET-BD2 in the aggressive MLL-AF9 AML model^[1].
GSK778 (15mg/kg/BID; s.c. for 14 days) reduces the production of anti-keyhole limpet hemocyanin (KLH) IgM and is well tolerated^[1].
GSK778 exhibits C_max (85 ng/mL), T_max (1.48 h) and AUC_∞ (132 ng.h/mL) following oral administration (10mg/kg) in mice^[1].

Animal Model:	6-8 weeks female C57BL/6 mice are injected with MLL-AF9 cells^[1]
Dosage:	15mg/kg/BID
Administration:	I.p. injections for 30 days
Result:	Increased the survival rate of leukemia mice.

Animal Model:	Male CD1 mice^[1]
Dosage:	10mg/kg (Pharmacokinetic Analysis)
Administration:	P.o. administration
Result:	C_max (85 ng/mL), T_max (1.48 h); AUC_∞ (132 ng.h/mL).

IC 50

BRD2 BD1: 75 nM (IC₅₀); BRD3 BD1: 41 nM (IC₅₀); BRD4 BD1: 41 nM (IC₅₀); BRDT BD1: 143 nM (IC₅₀)

References

[1] Omer G, et, al. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science. 2020 Apr 24; 368(6489): 387-394. DOI:10.1126/science.aaz8455