fusion was egfr cancer 9mg/m2/day. SNS314 SNS314 is a pan Aurora inhibitor with good affinity against all three isoforms and has selectivity over the majority of kinases. In keeping with other pan Aurora inhibitors, SNS314 potently blocks proliferation in a diverse panel of human cancer cell lines and leads to accumulation of cells with 4N DNA content. In xenograft models the compound blocks tumor growth at doses of 50 170mg/kg administered i.p. twice a week for 3 weeks. Apoptosis of tumor tissue along with inhibition of histone H3 phosphorylation in tumor, skin, and bone marrow is observed SNS314 is currently being assessed in a dose escalating phase I study in advanced solid tumors as an i.v. infusion given once a week for 3 weeks. CYC116 CYC116 is a pan Aurora kinase and VEGFR2 inhibitor .
It inhibits the spindle checkpoint and cytokinesis, resulting in polyploidy and induction of apoptosis. It has antitumor activity in various human solid tumors and leukemia xenograft models. CYC116 is presently in phase 1 clinical trail in advanced solid tumors and is orally bioavailable. Dar et al. Page 9 Mol Cancer Ther. Tandutinib Author manuscript, available in PMC 2011 February 2. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript PF 03814735 PF 03814735 is a novel oral ATP competitive, reversible inhibitor of Aurora A and B kinases with a broad spectrum of preclinical activity . In a study, 20 patients have received a median of 2 cycles across 7 dose levels from 5 100mg/day for five days. Tumor types included in the study were colorectal {5}, breast {3}, NSCLC {4}, SCLC {2}, bladder, melanoma, ovarian, renal, head and neck, and cancer of unknown primary.
The dose was doubled in single patient cohorts until treatment related grade 2 diarrhea occurred in one patient at 40 mg/day. Afterwards, cohorts included 3 7 patients with 20 50% dose increments per cohort. In the first 16 patients, the most common treatment related adverse events were mild to moderate diarrhea , vomiting , anorexia, fatigue, and nausea. Dose limiting febrile neutropenia was observed in 2/7 patients treated at 100mg/day. The maximum tolerated dose was defined as 80mg/day for five days. This dose level is currently being expanded to obtain proof of mechanism data at the recommended phase II dose.
Concluding Remarks The principal goal in the development of Aurora kinase inhibitors is to assess whether or not the administration of these small molecules to patients will yield a clinical benefit. For this reason, it is essential to answer several different questions, such as those regarding the effect of these inhibitors on other kinase proteins, the effect of the same drugs on the three different members of the Aurora kinase family, and the protein involved in Aurora kinase inhibition. For example, the interaction between Aurora kinase and p53 might select a patient for inclusion in the study according to the p53 status. On the other hand, recent studies indicate that AURKA inhibitors can activate p73 dependent apoptosis raising the possibility that these inhibitors may function irrespective of the p53 status.
Furthermore, it will be important to identify a safe dose for target inhibition in humans, tumor types that most likely respond to these drugs, reversibility of the effect on normal cells, and the dependence on this dose and duration of exposure. Neutropenia being the primary dose limiting phase I toxicity in several studies suggest that these agents have collateral anti proliferation toxicity on the bone marrow. Aurora kinase inhibitors induce polyploidy in normal mammary epithelial cell cultures , thus raising the issue of long term clinical effects. Clinical tolerability has generally been good, however, and no severe mucositis, peripheral n