GSK1070916性質(zhì)、用途與生產(chǎn)工藝
GSK1070916是一種可逆的，ATP競爭性的Aurora B/C抑制劑，IC50為3.5 nM/6.5 nM，比作用于緊密相關(guān)的Aurora A-TPX2復(fù)合體選擇性高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.
GSK1070916是一種可逆的，ATP競爭性的Aurora B/C抑制劑，IC50為3.5 nM/6.5 nM，比作用于緊密相關(guān)的Aurora A-TPX2復(fù)合體選擇性高100倍以上。 Phase 1。
| 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選擇性抑制Aurora B和Aurora C，K
i
為0.38 nM和1.5 nM，而作用于Aurora A 的K
i
為490 nM。Aurora B和Aurora C的抑制是時間依賴性的，酶抑制解離半衰期分別為>480 min和270 min。此外，GSK1070916也是ATP競爭性抑制劑。 GSK1070916處理人腫瘤細(xì)胞，劑量依賴性抑制Aurora B特異性底物，絲氨酸10上組蛋白H3的磷酸化。此外，GSK1070916抑制腫瘤細(xì)胞的增殖，在超過100種廣泛腫瘤類型的細(xì)胞系中，EC50 <10 nM，中值EC50為8 nM。雖然GSK1070916對增殖細(xì)胞具有有效活性，但是效能在原代，不分裂的，正常人血管內(nèi)皮細(xì)胞中顯著變化。此外，GSK1070916-處理的細(xì)胞不會停滯在有絲分裂期，而使其不能分裂，變?yōu)槎啾扼w，最終導(dǎo)致細(xì)胞凋亡。在另一項研究中，據(jù)報道，高水平染色體數(shù)與抗Aurora B與C的抑制相關(guān)，表明具有繞開高倍性檢查點機(jī)制的細(xì)胞對GSK1070916耐藥。
GSK1070916(25，50，或100 mg/kg)在小鼠體內(nèi)劑量依賴性抑制Aurora B特定底物的磷酸化作用，與其廣泛的細(xì)胞活性相一致，在10種人腫瘤異種移植模型中，包括乳腺，結(jié)腸，和兩種白血病模型中具有抗腫瘤作用。
GSK1070916
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