Polycomb-repressive complex 1 (PRC1) is a histone H2A/H2AX E3 ubiquitin ligase. PRC1 has a critical role in the regulation of differentiation and the maintenance of stem cell populations[2]. PRT4165 is a potent inhibitor of PRC1-mediated H2A ubiquitylation that inhibits the PRC1 subunits BMI1/RING1 with IC50 value of 3.9μM[3]. In vitro, treatment with 50μM PRT4165 in A375 cells or 100μM in Hela cells for 3h leaded to disappearance of the speckled staining in the nuclei and appearance of Bmi1 also in the cytoplasm[3]. PRT4165 inhibited H2AUB and sphere formation with IC50 values of 3.52mM and 1.05mM in PC3 cells [4]. Treatment PRT4165 at dose of 50μM PRT4165 suppressed growth of leukemia cell lines THP-1, TMD7, OCI/AML772, OCI/AML5, Jurkat and KOPT-K1 by apoptosis. In addition, PRT4165 inhibited the expression of NOTCH1 in KOPT-K1, OCI/ALML2 and OCI/AML5 cells. PRT4165 also inhibited the expression of NOTCH1, MYC, and HES1 in KOPT-K1 cells[5]. In vivo, administration of 8mg/kg PRT4165 caused disruption of decidualization and polyploidy development during early pregnancy by inhibition of PRC1 in mice[6].
作用机制
PRT4165 inhibits PRC1-mediated histone H2A ubiquitylation and the accumulation of ubiquitin at the DNA double-strand break sites [2].
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