LY2603618 - CAS 911222-45-2
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Not Intended for Therapeutic Use. For research use only.
Checkpoint Kinase (Chk)
LY2603618 is a potent and selective small molecule inhibitor of Chk1 protein kinase activity in vitro (IC50=7 nM) and the first selective Chk1 inhibitor to enter clinical cancer trials.
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Solid powder
LY-2603618; LY 2603618; Rabusertib
1.Preclinical analyses and phase I evaluation of LY2603618 administered in combination with pemetrexed and cisplatin in patients with advanced cancer.
Calvo E1, Chen VJ, Marshall M, Ohnmacht U, Hynes SM, Kumm E, Diaz HB, Barnard D, Merzoug FF, Huber L, Kays L, Iversen P, Calles A, Voss B, Lin AB, Dickgreber N, Wehler T, Sebastian M. Invest New Drugs. 2014 Oct;32(5):955-68. doi: 10.1007/s10637-014-0114-5. Epub 2014 Jun 20.
LY2603618 is an inhibitor of checkpoint kinase 1 (CHK1), an important regulator of the DNA damage checkpoints. Preclinical experiments analyzed NCI-H2122 and NCI-H441 NSCLC cell lines and in vitro/in vivo models treated with pemetrexed and LY2603618 to provide rationale for evaluating this combination in a clinical setting. Combination treatment of LY2603618 with pemetrexed arrested DNA synthesis following initiation of S-phase in cells. Experiments with tumor-bearing mice administered the combination of LY2603618 and pemetrexed demonstrated a significant increase of growth inhibition of NCI-H2122 (H2122) and NCI-H441 (H441) xenograft tumors. These data informed the clinical assessment of LY2603618 in a seamless phase I/II study, which administered pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) and escalating doses of LY2603618: 130-275 mg. Patients were assessed for safety, toxicity, and pharmacokinetics. In phase I, 14 patients were enrolled, and the most frequently reported adverse events included fatigue, nausea, pyrexia, neutropenia, and vomiting.
2.Evaluation of the likelihood of a selective CHK1 inhibitor (LY2603618) to inhibit CYP2D6 with desipramine as a probe substrate in cancer patients.
Hynes SM1, Wickremsinhe E, Zhang W, Decker R, Ott J, Chandler J, Mitchell M. Biopharm Drug Dispos. 2015 Jan;36(1):49-63. doi: 10.1002/bdd.1922. Epub 2014 Nov 14.
LY2603618 is a selective inhibitor of deoxyribonucleic acid damage checkpoint kinase 1 (CHK1) and has been in development for the enhancement of chemotherapeutic agents. The study described was to assess the potential interaction between LY2603618 and cytochrome P450 isoform 2D6 (CYP2D6) substrate desipramine in patients with cancer. Before clinical investigation, in silico simulations (using Simcyp®) were conducted. An open-label, two-period, fixed-sequence study was planned in 30 patients with advanced or metastatic cancers, in which a 50 mg oral dose of desipramine was administered alone and in combination with 275 mg of LY2603618 (i.v. infusion). An interim analysis was planned after 15 patients completed both periods. Ratios of geometric least squares means (LSMs) of primary pharmacokinetic (PK) parameters and 90% repeated confidence intervals (RCIs) between desipramine plus LY2603618 and desipramine alone were calculated. Lack of an interaction was declared if the 90% RCI fell between 0.
3.Phase I study of LY2603618, a CHK1 inhibitor, in combination with gemcitabine in Japanese patients with solid tumors.
Doi T1, Yoshino T, Shitara K, Matsubara N, Fuse N, Naito Y, Uenaka K, Nakamura T, Hynes SM, Lin AB. Anticancer Drugs. 2015 Nov;26(10):1043-53. doi: 10.1097/CAD.0000000000000278.
This phase I trial evaluated LY2603618, a selective inhibitor of the DNA damage checkpoint kinase 1, in combination with gemcitabine. Japanese patients with advanced solid tumors were enrolled. All patients received gemcitabine (1000 mg/m on days 1, 8, and 15 every 28 days) and either 170 mg (cohort 1) or 230 mg (cohort 2) of LY2603618. The primary objective was assessment of safety/tolerability. Pharmacokinetic/pharmacodynamic marker profiles were secondary objectives. Of the 17 patients enrolled, dose-limiting toxicities were observed in one patient in cohort 1 (n=7) and in two patients in cohort 2 (n=10). The most common grade 3 or more drug-related treatment-emergent adverse events were hematological. Three patients discontinued because of adverse events. Dose-dependent decreases in LY2603618 exposure were observed, but the LY2603618 pharmacokinetics at each dose were consistent within and between cycles and did not influence gemcitabine pharmacokinetics.
4.LY2603618, a selective CHK1 inhibitor, enhances the anti-tumor effect of gemcitabine in xenograft tumor models.
Barnard D1, Diaz HB1, Burke T1, Donoho G1, Beckmann R1, Jones B1, Barda D1, King C1, Marshall M2. Invest New Drugs. 2016 Feb;34(1):49-60. doi: 10.1007/s10637-015-0310-y. Epub 2015 Nov 27.
Pharmacological inhibition of CHK1 in the absence of p53 functionality leads to abrogation of the S and G2/M DNA damage checkpoints. We report the preclinical therapeutic activity of LY2603618 (CHK1 inhibitor) at inhibiting CHK1 activation by gemcitabine and enhancing in vivo efficacy. The in vivo biochemical effects of CHK1 inhibition in the absence or presence of DNA damage were measured in human tumor xenograft models. Colon, lung and pancreatic xenografts models were treated with gemcitabine, LY2603618, or gemcitabine plus LY2603618. Gemcitabine treatment alone induced a significant increase in CHK1 autophosphorylation over untreated tumors. Co-administration of LY2603618 with gemcitabine showed a clear inhibition of CHK1 autophosphorylation for at least 24 h. Combining LY2603618 with gemcitabine resulted in an increase in H2AX serine 139 phosphorylation, indicating a corresponding increase in damaged DNA in the tumors. LY2603618 abrogated the S-phase DNA damage checkpoint in Calu-6 xenograft tumors treated with gemcitabine but did not significantly alter the G2/M checkpoint.
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CAS 911222-45-2 LY2603618

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