mk-8776 and Neoplasms

It is widely recognized that the evasion of apoptotic cell death is one of the hallmarks of cancer. For many years cytotoxic agents have been developed to target apoptotic cell death as a main method of treating cancer. However, the occurrence of cellular defects involving the apoptotic machinery in many cancers has resulted in an acquired resistance to apoptotic cell death, undermining the effectiveness of chemotherapeutic agents. Over the past decade, research has revealed a growing number of cell death pathways that are not dependent on apoptosis. In addition, compounds specifically triggering these alternative cell death pathways have been identified and explored as novel cancer treatment options. These novel anticancer agents are critically discussed by the authors, and therefore, the current Perspective represents a resource for a practicing medicinal chemist looking for new opportunities to combat cancers resistant to the established proapoptotic therapeutic agents.

Topics: Antineoplastic Agents; Cell Death; Humans; Lysosomes; Neoplasms

We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies.. Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m(2) as monotherapy and then in combination with gemcitabine 800 mg/m(2) (part A, n = 26) or gemcitabine 1,000 mg/m(2) (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine.. As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease.. MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Checkpoint Kinase 1; Cohort Studies; Cytarabine; Deoxycytidine; Female; Gemcitabine; Histones; Humans; Infusions, Intravenous; K562 Cells; Male; Melanoma; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Pyrazoles; Pyrimidines; Sarcoma; Time Factors

DNA damage activates Checkpoint kinase 1 (Chk1) to halt cell cycle progression thereby preventing further DNA replication and mitosis until the damage has been repaired. Consequently, Chk1 inhibitors have emerged as promising anticancer therapeutics in combination with DNA damaging drugs, but their single agent activity also provides a novel approach that may be particularly effective in a subset of patients. From analysis of a large panel of cell lines, we demonstrate that 15% are very sensitive to the Chk1 inhibitor MK-8776. Upon inhibition of Chk1, sensitive cells rapidly accumulate DNA double-strand breaks in S phase in a CDK2- and cyclin A-dependent manner. In contrast, resistant cells can continue to grow for at least 7 days despite continued inhibition of Chk1. Resistance can be circumvented by inhibiting Wee1 kinase and thereby directly activating CDK2. Hence, sensitivity to Chk1 inhibition is regulated upstream of CDK2 and correlates with accumulation of CDC25A. We conclude that cells poorly tolerate CDK2 activity in S phase and that a major function of Chk1 is to ensure it remains inactive. Indeed, inhibitors of CDK1 and CDK2 arrest cells in G1 or G2, respectively, but do not prevent progression through S phase demonstrating that neither kinase is required for S phase progression. Inappropriate activation of CDK2 in S phase underlies the sensitivity of a subset of cell lines to Chk1 inhibitors, and this may provide a novel therapeutic opportunity for appropriately stratified patients.

Topics: Antineoplastic Agents; cdc25 Phosphatases; Cell Line, Tumor; Checkpoint Kinase 1; Cyclin A; Cyclin E; Cyclin-Dependent Kinase 2; DNA Breaks, Double-Stranded; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Activation; Histones; Humans; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrimidinones; S Phase Cell Cycle Checkpoints; Signal Transduction; Time Factors

Topics: Checkpoint Kinase 1; Deoxycytidine; Female; Gemcitabine; Humans; Male; Neoplasms; Protein Kinases; Pyrazoles; Pyrimidines