化学性质：                                                                                                             

产品描述：                                                                                                             

CPI-1612 is a highly potent, orally active EP300/CBP histone acetyltransferase (HAT) inhibitor with an IC50 of 8.1 nM for EP300 HAT. CPI-1612 has an anticancer activity[1].

CPI-1612 inhibits full length EP300 and full length CBP with IC50 values <0.5 nM and 2.9 nM, respectively[1].CPI-1612 inhibits H3K18Ac MSD (H3K18 = histone 3 lysine 18, MSD = meso scale discovery) and JEKO-1 cell proliferation with with IC50 values 14 nM and <7.9 nM, respectively[1].CPI-1612 (compound 17) shows weak activity in a hERG binding assay (IC50 = 10.4 μM) and displayed moderate inhibition of CYP2C8 (IC50 = 1.9 μM) and CYP2C19 (IC50 = 2.7 μM)[1].

CPI-1612 (compound 17; 0.5 mg/kg; oral administration; twice a day; for 4 weeks) treatment shows 67% tumor growth inhibition (TGI) with concomitant reduction of H3K27Ac in plasma and reduction of H3K18Ac in the tumor[1].While the oral exposure of CPI-1612 (compound 17) in dogs (0.5 mg/kg IV; 1.0 mg/kg PO; clearance = 0.42 L/h/kg, Vss = 3.7 L/kg, T1/2 = 5.5 h, F% = 71; AUC/dose = 1691 h.mg/mL) and mice (1 mg/kg IV; 5 mg/kg PO; clearance = 3.8 L/h/kg, Vss = 2.0 L/kg, T1/2 = 0.98 h, F% = 79; AUC/dose = 211 h.mg/mL) is good, the exposure in rats is limited by poor bioavailability (1.0 mg/kg IV; 5.0 mg/kg PO; clearance = 2.6 L/h/kg, Vss = 1.8 L/kg, T1/2 = 1.2 h, F% = 9; AUC/dose = 35.6 h.mg/mL)[1].A single dose of CPI-1612 is administered orally to CD-1 mice and brain and plasma exposures of CPI-1612 are measured at 0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 h. CPI-1612 is highly brain-penetrant, showing a brain-to-plasma ratio of 0.35 after a single oral dose[1].

[1]. Jonathan E Wilson, et al. Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor. ACS Med Chem Lett. 2020 Apr 23;11(6):1324-1329..

特别提醒：