enmd-2076 and Neoplasms

The Aurora kinase family of kinases (Aurora A, B, and C) are involved in multiple mitotic events, and aberrant expression of these kinases is associated with tumorigenesis. Aurora A and Aurora B are validated anticancer targets, and the development of Aurora kinase inhibitors has progressed from preclinical to clinical studies. A variety of Aurora A, B and pan-Aurora kinase inhibitors have entered the clinic. The main side effects include febrile neutropenia, stomatitis, gastrointestinal toxicity, hypertension, and fatigue. Responses including complete remissions have been described in diverse, advanced malignancies, most notably ovarian cancer and acute myelogenous leukemia. This review highlights the biologic rationale for Aurora kinase as a target, and clinical trials involving Aurora kinase inhibitors, with particular emphasis on published early phase studies, and the observed anti-tumor activity of these agents.

Topics: Antineoplastic Agents; Aurora Kinase A; Aurora Kinase B; Aurora Kinases; Benzamides; Benzazepines; Benzimidazoles; Clinical Trials as Topic; Heterocyclic Compounds, 3-Ring; Humans; Molecular Targeted Therapy; Neoplasms; Norbornanes; Organophosphates; Piperazines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Quinazolines; Urea

Topics: Animals; Antineoplastic Agents; Aurora Kinases; Drug Discovery; Humans; Mitosis; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases

ENMD-2076 is a unique orally bioavailable Aurora kinase and VEGFR inhibitor. The purpose of this phase 1 study of ENMD-2076 was to determine the MTD, pharmacokinetic, and pharmacodynamic profiles and preliminary antitumor activity.. Patients with refractory advanced solid malignancies were treated with ENMD-2076 orally with continuous once daily dosing. Doses from 60 to 200 mg/m(2) were evaluated using a standard 3 (to 4) + 3 design. Pharmacokinetic parameters were studied on days 1, 28, and 30 to 35 of cycle 1. Expanded MTD cohorts included patients with ovarian cancer, colorectal cancer, and refractory solid tumors.. A total of 67 patients (46 F, 21M; ages 30-76) entered the study. Dose levels of 60, 80, 120, 200, and 160 mg/m(2) were evaluated. Two patients experienced grade 3 hypertension at 200 mg/m(2), and additional grade 3 neutropenia events limited tolerability at this dose. An intermediate dose of 160 mg/m(2) was determined to be the MTD. The most common drug-related adverse events included hypertension, nausea/vomiting, and fatigue. The pharmacokinetics of ENMD-2076 were characterized by a rapid absorption phase (T(max) 3-7.8 hours), a t(1/2) of 27.3 to 38.3 hours after a single dose, and dose proportional exposure. Decreased plasma sVEGFR2 was observed posttreatment. Two patients with platinum refractory/resistant ovarian cancer had RECIST partial responses.. ENMD-2076 was well tolerated, had a linear pharmacokinetic profile, and showed promising antitumor activity, particularly in ovarian cancer. The recommended phase 2 dose of ENMD-2076 is 160 mg/m(2) administered orally once daily with continuous dosing.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Aurora Kinases; Dose-Response Relationship, Drug; Female; Histones; Humans; Hypertension; Keratinocytes; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Protein Serine-Threonine Kinases; Pyrazoles; Pyrimidines; Treatment Outcome; Tumor Burden; Vascular Endothelial Growth Factor Receptor-2

Topics: Animals; Antineoplastic Agents; Aurora Kinase A; Aurora Kinase B; Azepines; Cell Line, Tumor; Humans; Mice; Mice, Nude; Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Vascular Endothelial Growth Factor Receptor-2

The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.

Topics: Animals; Antineoplastic Agents; Aurora Kinase A; Aurora Kinase B; Aurora Kinase C; Aurora Kinases; Benzimidazoles; Female; HCT116 Cells; Humans; Mice, SCID; Models, Chemical; Models, Molecular; Molecular Structure; Neoplasms; Protein Binding; Protein Kinase Inhibitors; Protein Structure, Tertiary; Quinolones; Sf9 Cells; Small Molecule Libraries; Xenograft Model Antitumor Assays