PTC596 is an orally active and selective B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) inhibitor. PTC596 targets BMI1 expressed by both tumor cells and cancer stem cells (CSCs), and induces hyper-phosphorylation of BMI1, leading to its degradation. PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells[1][2].
B-cell specific Moloney murine leukemia virus integration site 1 (BMI-1) has pleiotropic function in several cellular processes, including DNA damage, apoptosis, senescence, and self-renewal of stem cells. BMI-1 also plays a central role in cancer stem cell growth and survival in various neoplasia, PTC596 is a small molecule selective inhibitor of BMI1. PTC596 can inhibited proliferation of mantle cell lymphoma (MCL) cell lines, including REC-1, NCEB-1, MINO, MAVER-1, JVM-2, Granta-519, Jeko-1, and Z-138 with IC50 values ranging in 68-340 nM and EC50 values ranging in 150-507 nM, PTC596 at concentration of 300 nM induced activation, caspase-3 cleavage, mitochondrial membrane potential loss and MCL-1 levels decreased in Z-138 and REC-1 cells. These data suggested PTC596 induces mitochondrial apoptosis in MCL cells through down-regulation of MCL-1[1]. PTC596 at concentration of 0.1 and 1μM reduced cell viability and induced a G2M arrest in human PDA lines Aspc1, Mia PaCa-2, and Panc1. PTC596 also induced the M-phase marker phospho-histone H3 (PH3) accumulation in these PDA cells. These data demonstrated that PTC596 acts as a potent inducer of mitotic arrest in multiple PDA cell lines[2]. In vivo, administration of PTC596 at 15 mg/kg twice weekly led to a 48.9% reduction of bone marrow multiple myeloma infiltration and weekly treatment with PTC596 at a dose of 30 mg/kg led to a complete eradication of multiple myeloma cells in 5TGM.1 murine model of myeloma[3]. Oral administration of PTC596 at 12.5 mg/kg twice a week for 45 days slowed tumor growth modestly in nu/nu mice bearing Capan-1 xenograft tumors. Oral administration of 17 mg/kg PTC596 did not affect survival, but the combination of the PTC596 and gemcitabine in a synergistic way improved survival in nu/nu mice bearing Capan-1 xenograft tumors[2].
作用机制
PTC596 induces phosphorylation of BMI-1 at two N-terminal sites, leading to accelerated degradation of BMI-1[1].
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