942918-07-2

GSK1070916是一种可逆的，ATP竞争性的Aurora B/C抑制剂，IC50为3.5 nM/6.5 nM，比作用于紧密相关的Aurora A-TPX2复合体选择性高100倍以上。 Phase 1。

GSK1070916 selectively inhibits Aurora B and Aurora C with K_i of 0.38 nM and 1.5 nM over Aurora A with K_i of 490 nM. Inhibition of Aurora B and Aurora C is time-dependent, with an enzyme-inhibitor dissociation half-life of >480 min and 270 min respectively. In addition, GSK1070916 is also a competitive inhibitor with respect to ATP. Human tumor cells treated with GSK1070916 shows dose-dependent inhibition of phosphorylation on serine 10 of Histone H3, a substrate specific for Aurora B. Moreover, GSK1070916 inhibits the proliferation of tumor cells with EC50 values of <10 nM in over 100 cell lines spanning a broad range of tumor types, with a median EC50 of 8 nM. Although GSK1070916 has potent activity against proliferating cells, a dramatic shift in potency is observed in primary, nondividing, normal human vein endothelial cells. Furthermore, GSK1070916-treated cells do not arrest in mitosis but instead fails to divide and become polyploid, ultimately leading to apoptosis. In another study, it is also reported high chromosome number associated with resistance to the inhibition of Aurora B and C suggests cells with a mechanism to bypass the high ploidy checkpoint are resistant to GSK1070916.

GSK1070916 (25, 50, or 100 mg/kg) shows dose-dependent inhibition of phosphorylation of an Aurora B–specific substrate in mice and consistent with its broad cellular activity, has antitumor effects in 10 human tumor xenograft models including breast, colon, lung, and two leukemia models.

Target	Value
Aurora B-INCENP (Cell-free assay)	3.5 nM
Aurora C-INCENP (Cell-free assay)	6.5 nM
FLT1 (Cell-free assay)	42 nM
Tie-2 (Cell-free assay)	59 nM
SIK (Cell-free assay)	70 nM

GSK1070916选择性抑制Aurora B和Aurora C，K _i 为0.38 nM和1.5 nM，而作用于Aurora A 的K _i 为490 nM。Aurora B和Aurora C的抑制是时间依赖性的，酶抑制解离半衰期分别为>480 min和270 min。此外，GSK1070916也是ATP竞争性抑制剂。 GSK1070916处理人肿瘤细胞，剂量依赖性抑制Aurora B特异性底物，丝氨酸10上组蛋白H3的磷酸化。此外，GSK1070916抑制肿瘤细胞的增殖，在超过100种广泛肿瘤类型的细胞系中，EC50 <10 nM，中值EC50为8 nM。虽然GSK1070916对增殖细胞具有有效活性，但是效能在原代，不分裂的，正常人血管内皮细胞中显著变化。此外，GSK1070916-处理的细胞不会停滞在有丝分裂期，而使其不能分裂，变为多倍体，最终导致细胞凋亡。在另一项研究中，据报道，高水平染色体数与抗Aurora B与C的抑制相关，表明具有绕开高倍性检查点机制的细胞对GSK1070916耐药。

GSK1070916(25，50，或100 mg/kg)在小鼠体内剂量依赖性抑制Aurora B特定底物的磷酸化作用，与其广泛的细胞活性相一致，在10种人肿瘤异种移植模型中，包括乳腺，结肠，和两种白血病模型中具有抗肿瘤作用。