Rabusertib (IC-83) is an inhibitor of the cell cycle checkpoint kinase 1 (chk1) with potential chemopotentiating activity. Rabusertib has been used in trials studying the treatment of Cancer, Solid Tumors, Advanced Cancer, Pancreatic Neoplasms, and Non-Small Cell Lung Cancer.

Chk1:7 nM

Chk1是一个依赖ATP的丝氨酸-苏氨酸激酶，是由双链断裂(DSBs)激活的DNA复制监控检查点系统的关键成分。Chk1对所有当前定义的细胞周期检查点，包括G1/S、S期内、G2/M以及有丝分裂纺锤体检查点，都有贡献。通过抑制chk1的活性，Rabusertib阻止了DNA损伤修复过程，从而增强了各种化疗化合物的抗肿瘤效果。然而，关于Rabusertib的临床前数据直到现在还未发布。[1]预计抑制Chk1会增强抗代谢物的效果，例如gemcitabine。[2]Rabusertib治疗会损害DNA合成，增加DNA损伤（通过有丝分裂缺陷），诱导细胞凋亡，特别是在p53突变的肿瘤细胞中，与pemetrexed有协同作用。[3]

在异种移植模型中，LY2603618与pemetrexed联合应用时可延缓肿瘤生长。[3]

Protein kinase assays are performed variously. Assays are performed on the following protein kinases: ABL, AKT1, ARG, CAMK2, CDK1, CDK2, CHK1, CHK2, DAPK1, EGFR, EPHA1, EPHB2, EPHB3, EPHB4, ERK1, ERK2, FES, FGFR1, FGFR3, FGFR4, FGR, HCK, HER2, INSR, JNK1, JNK2, LCK, MET, NTRK1, NTRK2, p38α, p38β, p38δ, p38γ, p70S6K, PDGFRα, PDGFRβ, PDK1, PKCα, ROCK2, ROS, RSK2, SGK1, SRC, SYK, TAK1, TYRO3, VEGFR2, VEGFR3, YES, ZAP70[1].

LY2603618 is prepared in DMSO (10 mM) and stock, and then diluted 1000-fold into medium[1]. Cells are plated at 2.5×103 per well, on 96-well tissue culture plates and incubated for one cell doubling (18-24 h). Gemcitabine dilutions are set up by half-log steps across a final concentration range of 1-1000 nM. LY2603618 is prepared by dilutions in DMSO to 5000× final concentration, and then diluted 1000-fold into medium to generate 5× stocks for addition to wells. Approximately 24 h after Gemcitabine addition, LY2603618 is added. Each combination is done in triplicate. After a period of two cell doublings following LY2603618 addition, MTS/PMS reagent is added to each well according to the manufacturer's instructions. Absorbance is read on a Spectra Max 250 spectrophotometer at 490 nm and the data analyzed with GraphPad Prism 4.0. Dose-response curves are fit by non-linear regression, with bottom fits constrained to 0 % inhibition[1].