LY2606368

LY2606368 is a selective ATP competitive inhibitor of checkpoint kinase 1(CHK1) with IC50 value of 1.5nM in SW1990 cells [1].

CHK1 is an intracellular serine/threonine kinase that plays a role in DNA damage response pathway. The inhibitors of CHK1 are developed for the treatment of cancers. LY2606368 is an ATP-competitive inhibitor of CHK1 and is undergoing clinical trials currently. It inhibits the auto-phosphorylation of CHK1 and induces the phosphorylation of H2AX in cancer cells. In the pancreatic cell line SW1990, LY2606368 significantly inhibits cell proliferation with IC50 value of 1.5nM. LY2606368 also exerts potent anti-tumor activity in SW1990 xenograft model. Besides that, in the orthotopic SKVO3 model, treatment of LY2606368 is found to inhibit tumor growth and reduce the incidence of metastases and accumulation. However, LY2606368 is only administered intravenously due to its poor oral bioavailability [1, 2 and 3].

References:
[1] Wu W, Bi C, Bence A K, et al. Antitumor activity of Chk1 inhibitor LY2606368 as a single agent in SW1990 human pancreas orthotopic tumor model. Cancer Research, 2012, 72(8 Supplement): 1776.
[2] Lainchbury M, Matthews T P, McHardy T, et al. Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino) pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors. Journal of medicinal chemistry, 2012, 55(22): 10229-10240.
[3] McNeely S C, Burke T F, DurlandBusbice S, et al. Abstract A108: LY2606368, a second generation Chk1 inhibitor, inhibits growth of ovarian carcinoma xenografts either as monotherapy or in combination with standard-of-care agents. Molecular Cancer Therapeutics, 2011, 10(Supplement 1): A108.

Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer.[Pubmed:27044938]

J Clin Oncol. 2016 May 20;34(15):1764-71.

PURPOSE: The primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy. PATIENTS AND METHODS: This phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m(2) on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m(2) on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells. RESULTS: Forty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m(2) (schedule 1) and 105 mg/m(2) (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically < 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC. CONCLUSION: An LY2606368 dose of 105 mg/m(2) once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC.

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms.[Pubmed:26141948]

Mol Cancer Ther. 2015 Sep;14(9):2004-13.

CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Here, we describe the characterization of a novel CHK1 inhibitor, LY2606368, which as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Loss of the CHK1-dependent DNA damage checkpoints permits cells with damaged DNA to proceed into early mitosis and die. The majority of treated mitotic nuclei consist of extensively fragmented chromosomes. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe. Changes in the ratio of RPA2 to phosphorylated H2AX following LY2606368 treatment further support replication catastrophe as the mechanism of DNA damage. LY2606368 shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. LY2606368 is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe.

Prexasertib (LY2606368) is a potent, selective and ATP-competitive checkpoint kinase 1 (Chk1) inhibitor, with an IC50 and a Ki of <1 nM and 0.9 nM, respectively.

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