NU 6102 is a potent CDK1 and CDK2 inhibitor with IC50 values of 9.5nM and 5.4nM for CDK1/cyclin B and CDK2/cyclin A3, respectively [1]. NU 6102 can induce the G2 arrest, inhibition of Rb phosphorylation, and cytotoxicity [2]. NU 6102 has been widely used to delay the growth of tumors in mice and inhibit the progression of xenograft tumors[3].
In vitro, NU 6102 treatment (10µM) for 72 hours significantly inhibited the proliferation of HCT116 cells[4]. Treatment with 25µM NU 6102 for 48 hours significantly increased the expression of p21 protein in BT483 cells and decreased the expression of Erb2 protein, and led to a significant decrease in cell viability[5]. Treatment with 25µM NU 6102 for 24 hours reduced the level of Mcl-1 and enhanced the apoptosis of chronic lymphocytic leukemia (CLL) cells mediated by LBH589[6].
In vivo, NU 6102 treatment via intraperitoneal injection at a dose of 100mg/kg twice daily for 10 days reduced the tumor volume in mice with HT29 xenografts[4].
References:
[1] Hardcastle I R, Arris C E, Bentley J, et al. N2-substituted O 6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2[J]. Journal of medicinal chemistry, 2004, 47(15): 3710-3722.
[2] Anscombe E, Meschini E, Mora-Vidal R, et al. Identification and characterization of an irreversible inhibitor of CDK2[J]. Chemistry & biology, 2015, 22(9): 1159-1164.
[3] Newell D, Thomas H, Wang L, et al. Preclinical in vitro and in vivo evaluation of the cyclin dependent kinase 2 inhibitor NU6102 and a water pro-drug NU6301[J]. Cancer Research, 2008, 68(9_Supplement): 2413-2413.
[4] Beale G, Haagensen E J, Thomas H D, et al. Combined PI3K and CDK2 inhibition induces cell death and enhances in vivo antitumour activity in colorectal cancer[J]. British journal of cancer, 2016, 115(6): 682-690.
[5] Chuang P Y, Huang C, Huang H C. The use of a combination of tamoxifen and doxorubicin synergistically to induce cell cycle arrest in BT483 cells by down-regulating CDK1, CDK2 and cyclin D expression[J]. Journal of Pharmaceutical Technology and Drug Research, 2013, 2(1): 12.
[6] Inoue S, Walewska R, Dyer M J S, et al. Downregulation of Mcl-1 potentiates HDACi-mediated apoptosis in leukemic cells[J]. Leukemia, 2008, 22(4): 819-825.
NU 6102是一种强效的CDK1和CDK2抑制剂，对CDK1/cyclin B和CDK2/cyclin A3的IC50值分别为9.5nM和5.4nM[1]。NU 6102可诱导G2期阻滞、抑制Rb磷酸化并产生细胞毒性[2]。NU 6102已被广泛用于延缓小鼠肿瘤生长并抑制异种移植肿瘤的进展[3]。
在体外，使用10μM的NU 6102处理HCT116细胞72小时，显著抑制了细胞增殖[4]。使用25μM的NU 6102处理BT483细胞48小时，显著增加了p21蛋白的表达，降低了Erb2蛋白的表达，并导致细胞活力显著下降[5]。使用25μM的NU 6102处理24小时，可降低慢性淋巴细胞白血病(CLL)细胞中Mcl-1的水平，并增强LBH589介导的细胞凋亡[6]。
在体内，每日两次腹腔注射100mg/kg剂量的NU 6102，连续10天，减少了携带HT29异种移植瘤小鼠的肿瘤体积[4]。