BMI-1 Expression Inhibitor, PTC-209

A cell-permeable imidazopyrimidinyl-thiazolamine compound that effectively downregulates cellular BMI-1 protein level both in cultures in vitro (IC₅₀ = 0.5 µM/48 h/HT1080 and <0.37 µM/HCT116/overnight) and in mice in vivo (4.5 ng vs.13.7 ng per mg HT1080 tumor tissue, respectively, with or without 10-d 60 mg/kg/d treatment via s.c.) by inhibiting BMI-1 transcription (IC₅₀ = 0.5 µM against overnight reporter transcription in HEK293) via a yet unidentified mechanism, thereby reducing BMI-1-dependent RING1A E3 ligase activity and RING1A-mediated H2A ubiquitination (uH2A)/epigenetic regulations. Shown to exhibit antiproliferation activity against human colon cancer cells both in cultures (IC₅₀<300 nM against LS174T and primary colon cancer cultures) in vitro and in mice (30 to 60 mg/kg/d s.c.) in vivo by inducing cell cycle arrest at G₀ and apoptosis. Reduced frequency of sphere-forming cells is observed among surviving cells (by 1.7- to 2.2-fold) upon PTC-209 removal post a 4-day 0.1 µM drug treatment period in primary colon cancer cultures, indicating a greater impact of drug treatment on self-renewing cancer-initiating cells (CICs; cancer stem cells). Likewise, surviving colon cancer cells from tumor-bearing mice at the end of drug treatment are shown to contain reduced population of tumor-initiating cells when xenografted into secondary recipient mice.

A cell-permeable imidazopyrimidinyl-thiazolamine compound that effectively downregulates cellular BMI-1 protein level both in cultures in vitro (IC₅₀ = 0.5 µM/48 h/HT1080 and <0.37 µM/HCT116/overnight) and in mice in vivo (60 mg/kg/d via s.c.) by inhibiting BMI-1 transcription via a yet unidentified mechanism, thereby reducing BMI-1-dependent RING1A E3 ligase activity and RING1A-mediated H2A ubiquitination (uH2A)/epigenetic regulations. Shown to exhibit antiproliferation activity against human colon cancer cells both in cultures (IC₅₀<300 nM) in vitro and in mice (30 to 60 mg/kg/d s.c.) in vivo via G0 cell cycle arrest and apoptosis induction with a greater drug impact on self-renewing cancer-initiating cells (CICs; cancer stem cells).

Cell permeable: yes

Reversible: no

Packaged under inert gas

Toxicity: Standard Handling (A)

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Kreso, A., et al. 2014. Nat. Med.20, 29.

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