arry-520 and Neoplasms

Cancer is considered as one of the most serious health problems. Despite the presence of many effective chemotherapeutic agents, their severe side effects together with the appearance of mutant tumors limit the use of these drugs and increase the need for new anticancer agents. Eg5 represents an attractive target for medicinal chemists since Eg5 is overexpressed in many proliferative tissues while almost no Eg5 is detected in nonproliferative tissues. Many Eg5 inhibitors displayed potent anticancer activity against some of the mutant tumors with limited side effects. The present review provides an overview about the progress in the discovery of Eg5 inhibitors especially from 2009 to 2012 as well as the clinical trials conducted on some of these inhibitors.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Drug Discovery; Humans; Kinesins; Models, Molecular; Molecular Structure; Neoplasms; Structure-Activity Relationship

Purpose Filanesib (ARRY-520) is a highly selective, targeted inhibitor of kinesin spindle protein (KSP) inhibitor that induces mitotic arrest and subsequent tumor cell death. This first-in-human Phase 1 study evaluated dose-limiting toxicities (DLTs) and determined a maximum tolerated dose (MTD) for filanesib administered as a 1-h intravenous infusion on 2 treatment schedules in patients with advanced solid tumors. The pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of filanesib were also evaluated. Methods Filanesib was administered on Day 1 of each 3-week cycle (Initial Schedule) or Days 1 and 2 of each 2-week cycle (Alternate Schedule). A standard 3 + 3 dose-escalation design was employed. An expansion cohort was conducted at the MTD of the Initial Schedule. Filanesib PK was evaluated in plasma (both schedules) and urine (Initial Schedule only). Monopolar spindle formation was evaluated in biopsies taken from patients in the expansion cohort. Results Forty-one patients received filanesib. The MTD was equivalent for both the Initial and Alternate Schedules (2.50 mg/m(2)/cycle). The prevalence of neutropenia as a DLT for both schedules necessitated adding prophylactic filgrastim to another dose escalation on the Alternate Schedule (highest tolerated dose 3.20 mg/m(2)/cycle). Neurotoxicity related to filanesib was not observed. Dose-proportional increases in filanesib exposure were observed. The half-life for filanesib was ~70 h. Monopolar spindles in patient biopsy samples indicated KSP inhibition. Stable disease was the best tumor response observed in 18 % (7/39) of evaluable patients. Conclusion Filanesib provided exposures with acceptable tolerability and evidence of target-specific pharmacodynamic effects.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Half-Life; Humans; Kinesins; Male; Maximum Tolerated Dose; Membrane Proteins; Middle Aged; Neoplasms; Thiadiazoles

Topics: Antineoplastic Agents; Biomarkers, Pharmacological; Clinical Trials as Topic; Humans; Kinesins; Molecular Targeted Therapy; Neoplasms; Pilot Projects; Thiadiazoles; Tubulin Modulators

Profiling the efficacy and pharmacodynamic activity of the kinesin spindle protein (KSP) inhibitor ARRY-520 will aid the identification of responsive tumor types and pharmacodynamic profiles that correlate with activity.. In vivo activity was evaluated in a diverse panel of 16 different tumor xenograft models. Pharmacodynamic activity was evaluated in selected models.. ARRY-520 had low nanomolar antiproliferative activity in tumor cell lines. Monopolar spindles were formed at active potencies. Partial or complete responses were observed in 13/16 xenograft models. Hematological tumors were particularly sensitive, with a 100% complete response rate in some models. Maintenance of mitotic block for a sufficient length of time for cells to lose survival signals and progress to apoptosis was a key component of the mechanism of activity. ARRY-520 was also active in several taxane resistant models.. The data provide a rationale for clinical evaluation of the activity of ARRY-520 in hematological carcinomas and taxane-resistant tumors.

Topics: Animals; Cell Growth Processes; Cell Lineage; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; HCT116 Cells; HeLa Cells; HL-60 Cells; HT29 Cells; Humans; Immunohistochemistry; K562 Cells; Kinesins; Mice; Mice, Inbred NOD; Mice, SCID; Mitosis; Neoplasms; Taxoids; Thiadiazoles; Xenograft Model Antitumor Assays