PTC-028

Research use only, not for human use.

PTC-028 (PTC028) is a novel potent, selective, orally bioavailable BMI-1 inhibitor with potent anti-MM activity against primary MM cells (IC50=10-100 nM).

PTC-028 (PTC028) is a novel potent, selective, orally bioavailable BMI-1 inhibitor with potent anti-MM activity against primary MM cells (IC50=10-100 nM); decreases BMI-1 levels by posttranslational modification, selectively inhibits cancer cells in clonal growth and viability assays (IC50=100 nM), without effeccts on normal cells; exhibits significant antitumor activity in mouse model of ovarian cancer.(In Vitro):PTC-028 (25-500 nM; 48 hours) significantly decreases CP20, OVCAR4 and OV90 epithelial ovarian cancer cells viability. However, in normal ovarian surface epithelial cells (OSE) and fallopian tube epithelial cells (FTE) cells, up to 500 nM treatment with PTC-028 for 48 hours has minimal effect (~18-30% decrease).PTC-028 (100 nM; 2-12 hours) increases the phosphorylated BMI-1 species in a time-dependent manner. PTC-028 subsequently reduces BMI-1 in the biochemical functional readout .uH2A is observed up to 12 h with PTC-028 (100 nM) in both CP20 and OV90 cells while total H2A levels remain unchanged .PTC-028 (100 nM; 48 hours) decreases the expression of XIAP and RIPK1 while LC3B levels remains unchanged compared to that of the control .Significant cleavage of Caspase 7, Caspase 9 and PARP is observed in PTC-028 (100 nM; 48 hours).(In Vivo):PTC-028 (15 mg/kg; administered orally twice weekly) causes ~94% (0.169 g) reduction in tumor weight compared to the control (average tumor weight, ~3g) .No obvious toxicity is noted in the animals during therapy experiments as assessed by mean body weight.PTC-028 (10 mg/kg or 20mg/kg; single oral doses) is administrated to the CD-1 mice. The Cmax is reached at both dose levels 1h post dose after which plasma concentrations slowly reduce.

Cell Viability Assay Cell Line:OVCAR4, OV90 and CP20 cells Concentration:0, 25, 50, 100, 200, 500 nM Incubation Time:48 hours Result:OVCAR4, OV90 and CP20 cells demonstrated significant dose dependent decrease in cell viability with an IC50 of ~100 nM and ~95% decrease at 500 nM. Western Blot Analysis Cell Line:OV90 and CP20 cells Concentration:100 nM Incubation Time:2, 4, 6, 12 hours Result:A time-dependent increase in the phosphorylated BMI-1 species and subsequent reduction in the biochemical functional readout.

Animal Model:Female athymic nude mice with implanted OV90 cellsDosage:15 mg/kg Administration:Orally administered; twice weekly Result:Caused ~94% (0.169 g) reduction in tumor weight. Animal Model:Female CD-1 mice Dosage:10 mg/kg or 20mg/kg Administration:Oral administered; single doseResult:Total plasma AUC0-24h were 10.9 and 26.1 μg?h/mL at doses of 10 and 20 mg/kg. The Cmax for PTC-028 at 10 and 20 mg/kg was 0.79 and 1.49 ug/mL, respectively.

PTC 028 | PTC028

Others

BMI-1

BMI-1

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1782970-28-8

405.332

C19H12F5N5

>98% (HPLC)

DMSO : 125 mg/mL 308.40 mM; H2O : < 0.1 mg/mL

FC(C1=CC=C(NC2=NC(N3C4=CC(F)=C(F)C=C4N=C3C)=CN=C2)C=C1)(F)F

6-(5,6-difluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine

(-20℃)

With Ice Pack

≥ 2 years