1.BMI-1026 treatment can induce SAHF formation by activation of Erk1/2.
Seo HJ1, Park HJ, Choi HS, Hwang SY, Park JS, Seong YS. BMB Rep. 2008 Jul 31;41(7):523-8.
BMI-1026 is a synthetic aminopyrimidine compound that targets cyclin dependent kinases (cdks) and was initially designed as a potential anticancer drug. Even though it has been well documented that BMI-1026 is a potent cdk inhibitor, little is known about the cellular effects of this compound. In this study, we examined the effects of BMI-1026 treatment on inducing premature senescence and then evaluated the biochemical features of BMI-1026-induced premature senescence. From these experiments we determined that BMI-1026 treatment produced several biochemical features of premature senescence and also stimulated expression of mitogen activated protein kinase (MAPK) family proteins. BMI-1026 treatment caused nuclear translocation of activated Erk1/2 and the formation of senescence associated heterochromatin foci in 5 days. The heterochromatin foci formation was perturbed by inhibition of Erk1/2 activation.
2.Characterization of a novel cyclin-dependent kinase 1 inhibitor, BMI-1026.
Seong YS1, Min C, Li L, Yang JY, Kim SY, Cao X, Kim K, Yuspa SH, Chung HH, Lee KS. Cancer Res. 2003 Nov 1;63(21):7384-91.
Cyclin-dependent kinases (Cdks) have been attractive targets for the development of anticancer therapeutic agents. In an effort to generate a new class of anti-Cdk inhibitors, we synthesized aryl aminopyrimidines and examined the effect of these compounds in both in vitro kinase assays and cultured cells. Two of these compounds, BMI-1026 and BMI-1042, induced a strong cell cycle alteration with potent inhibitory activities against cyclin-dependent kinases, collectively known as Cdks. Characterization of BMI-1026 revealed that it imposes a potent G(2)-M arrest and mild G(1)-S and S arrests. In vitro biochemical analyses and in vivo time-lapse microscopy studies revealed that it induces a mitotic catastrophe and precocious mitotic exit even in the presence of nocodazole. These defects appeared to lead to apoptotic cell death in tumorigenic cell lines. Consistent with the induction of mitotic defects and apoptosis, BMI-1026 imposed a selective sensitivity to proliferating versus differentiating or growth-arrested mouse keratinocytes.