ekb-569 and Neoplasms

Quinazoline was originally utilized as an anti-tumor treatment, and its various derivatives can be directly extracted from plants. In recent years, protein kinases (PK) have been well recognized in the development of tumor drugs. Functionally, PK serves a vital role in the apoptosis, proliferation, differentiation, migration and cell cycle of tumor cells. Due to its good physicochemical properties, quinazoline skeleton, a superior type of PK inhibitor, has been extensively used in anti-tumor drug design. An increasing number of studies on quinazoline synthesis have been reported and used by different groups to effectively develop novel derivatives. Thus, several studies have been approved for the use of quinazoline derivatives as inhibitors of other kinases, including Src and histone deacetylase. The aim of the present review was to summarize the mechanism of quinazoline compounds as PK inhibitors, their biological structure-activity relationship such as the substituted quinazoline compounds with different functional groups in the apoptotic process, and their effect on the proliferation of tumor cells. The development of novel agents based on the antitumor functions of quinazoline molecular compounds may improve the clinical outcomes of the affected population, particularly in patients with cancer.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Quinazolines

The global incidence of cancer is on the rise, and within the next decade, the disease is expected to become the leading cause of death worldwide. Forthcoming strategies used to treat cancers focus on the design and implementation of multidrug therapies to target complementary cancer specific pathways. A more direct means by which this multitargeted approach can be achieved is by identifying and targeting interpathway regulatory factors. Recent advances in understanding Nek2 (NIMA related kinase 2) biology suggest that the kinase potentially represents a multifaceted therapeutic target. In this regard, pharmacologic modulation of Nek2 with a single agent may effect several mechanisms important for tumor growth, survival, progression, and metastasis. We herein review the development of Nek2 as an oncology target and provide a succinct chronology of drug discovery campaigns focused on targeting Nek2.

Topics: Drug Discovery; Humans; Models, Molecular; Molecular Conformation; Neoplasms; NIMA-Related Kinases; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Small Molecule Libraries

The development of HKI-272 and EKB-569 for the treatment of cancer is described. These compounds function as irreversible inhibitors of some members of the ErbB family of receptor tyrosine kinases. In particular, they target epidermal growth factor receptor (EGFR, also known as ErbB-1) and human epidermal growth factor receptor-2 (HER2, also known as ErbB-2). Both, HKI-272 and EKB-569 are 4-anilino-3-cyano quinoline derivatives that contain a 4-(dimethylamino)crotonamide Michael-acceptor group at the 6-position. These compounds inhibit the function of the target enzymes by forming a covalent interaction with a conserved cysteine residue located in the kinase domains of these proteins. The potential advantages of using irreversible inhibitors for this purpose are discussed. We summarize the recent findings concerning some somatic mutations in EGFR and their relevance with respect to the irreversible inhibitors. In particular, we highlight the findings that these irreversible inhibitors retain activity against tumors that have acquired a resistance to the reversible binding inhibitors gefitinib and erlotinib. The promising interim clinical trial results for HKI-272 and EKB-569 in treating colon, lung, and breast cancers are summarized.

Topics: Aminoquinolines; Aniline Compounds; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Colonic Neoplasms; Drug Screening Assays, Antitumor; ErbB Receptors; Female; Humans; Lung Neoplasms; Neoplasms; Quinolines; Receptor, ErbB-2

Specific and reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib are clinically active in advanced or metastatic NSCLC and both are approved in various countries for the treatment of patients that failed prior chemotherapy. Erlotinib has also prolonged survival in pancreatic cancer patients when added to gemcitabine and regulatory approval in this disease is being sought. Additional promising activity has been seen in other tumor types, such as ovarian cancer or head and neck malignancies, and phase III trials in these malignancies are ongoing or planned. Despite these successes, these agents have exhibited anecdotal or modest activity when used as single agents in unselected patients with various other tumor types. We have learned that the clinical development of these agents is far from simple and we need to better understand biological and clinical criteria for patient selection and how to best use the different available agents. The recent discovery of EGFR mutations and the potential identification of other markers that might predict patient response could help to optimize the use of these agents in the future. Irreversible EGFR inhibitors, dual EGF/HER2 and pan-ErbB receptor inhibitors may have greater antitumor activity although the tolerance of these compounds compared to specific EGFR TKIs needs further characterization. HER2 specific TKIs are also in development. Lapatinib, a dual EGFR/HER2 TK inhibitors, is particularly promising in breast cancer. Newer agents, such as BMS-599626, have recently entered into the clinic. In addition to the use of these agents as single agents, many clinical studies are addressing the role of combining them with hormonal agents, biological agents or chemotherapy.

Topics: Aminoquinolines; Aniline Compounds; Animals; Antineoplastic Agents; Clinical Trials as Topic; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Intracellular Signaling Peptides and Proteins; Mutation; Neoplasms; Organic Chemicals; Quinazolines; Signal Transduction

Progress in identifying and understanding the molecular and cellular causes of cancer has led to the discovery of anomalies that characterize cancer cells and that represent targets for the development of cancer therapeutics. One such target is the epidermal growth factor receptor (EGFR), a transmembrane protein that is frequently dysregulated in cancer cells. Preclinical studies have demonstrated that pharmacologic interventions that abrogate EGFR dysfunction result in antitumor effects. On the basis of these findings, therapeutic strategies to inhibit EGFR and EGFR-related pathways, including the use of monoclonal antibodies against the extracellular ligand-binding domain of EGFR and small-molecule inhibitors of the tyrosine kinase activity of EGFR, have entered clinical testing where they have demonstrated favorable safety profiles and adequate clinical pharmacology. Further development of these agents has been fueled by evidence of their antitumor activities, both as single agents and in combination with chemotherapy and radiation therapy. Areas that require investigation are the definition of patient populations most likely to derive benefits from these drugs, the implementation of biologic correlative studies to aid the selection of pharmacodynamically relevant doses and schedules, the characterization of population pharmacokinetic parameters and pharmacogenomic variables, and the most appropriate clinical scenario for proceeding with the clinical development of these agents.

Topics: Aminoquinolines; Aniline Compounds; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; Clinical Trials as Topic; Drug Design; Drugs, Investigational; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Gene Expression Regulation, Neoplastic; Humans; Morpholines; Neoplasms; Organic Chemicals; Panitumumab; Pyrimidines; Pyrroles; Quinazolines; Signal Transduction; Structure-Activity Relationship

Purpose Activation of EGFR can stimulate proliferative and survival signaling through mTOR. Preclinical data demonstrates synergistic activity of combined EGFR and mTOR inhibition. We undertook a phase I trial of temsirolimus (T, an mTOR inhibitor) and EKB-569 (E, an EGFR inhibitor) to determine the safety and tolerability. Methods The primary aim was to determine the maximally tolerated dose (MTD) of this combination in adults with solid tumors. Following the dose-escalation phase, (Cohort A), two subsequent cohorts were used to assess any pharmacokinetic (PK) interaction between the agents. Results Forty eight patients were enrolled. The MTD of this combination was E, 35 mg daily and T, 30 mg on days 1-3 and 15-17 using a 28-day cycle. The most common toxicities were nausea, diarrhea, fatigue, anorexia, stomatitis, rash, anemia, neutropenia, thrombocytopenia, and hypertriglyceridemia. Sixteen patients (36%) had at least one grade 3 toxicity. The most frequent grade 3/4 toxicities were diarrhea, dehydration, and nausea and vomiting (19% each). No grade 5 events were seen. Four patients had a partial response and 15 had stable disease. Clinical benefit was seen across a range of tumor types and in all cohorts. PK analysis revealed no significant interaction between E and T. Conclusions This combination of agents is associated with tolerable toxicities at doses that induced responses. PK studies revealed no interaction between the drugs. Further investigations of this targeting strategy may be attractive in renal cell carcinoma, non-small cell lung cancer, alveolar sarcoma, and carcinoid tumor.

Topics: Adult; Aged; Aged, 80 and over; Aminoquinolines; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; ErbB Receptors; Female; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

The maximum tolerated dose (MTD) and the dose-limiting toxicities of EKB-569, a selective, irreversible inhibitor of the epidermal growth factor receptor (EGFR), when administered orally once daily on an intermittent-dose schedule (14 days of a 28-day cycle) or on a continuous-dose schedule (each day of a 28-day cycle), were determined in patients with advanced solid tumors.. Planned dose escalation was 25, 50, 75, 125, 175, and 225 mg. Pharmacokinetic sampling was performed on days 1 and 14 for the intermittent-dose cohort and on days 1 and 15 for the continuous-dose cohort.. Thirty patients received a median of two cycles (range, one to 10 cycles) in the intermittent-dose cohort; 29 patients received a median of three cycles (range, one to eight cycles) in the continuous-dose cohort. Dose-limiting toxicity was grade 3 diarrhea, and the MTD was 75 mg EKB-569 per day for both cohorts. Other common toxicities included rash, nausea, and asthenia. Exposure to EKB-569 was dose proportional. At the MTD, the mean +/- standard deviation terminal half-life was 21.7 +/- 4.2 hours and peak concentration increased 1.2-fold from day 1 to day 14/15. No major antitumor responses were observed. However, one patient with non-small-cell lung cancer and one with cutaneous squamous cell carcinoma had stable disease for 33 and 24 weeks, respectively.. The MTD of once-daily oral EKB-569 is 75 mg. The tolerable toxicity profile and long half-life of this irreversible EGFR inhibitor warrant its further evaluation as a single agent and in combination with other drugs.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Aminoquinolines; Aniline Compounds; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; ErbB Receptors; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organic Chemicals

Topics: Aminoquinolines; Aniline Compounds; Antibodies, Monoclonal; Antineoplastic Agents; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Mutation; Neoplasms; Organic Chemicals; Protein Kinase Inhibitors; Quinazolines

To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved "gatekeeper" threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib- and BMS-354825-resistant ABL(T315I) kinase. The KIT/FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D/T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitinib- and erlotinib-resistant EGFR(L858R/T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib/erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of next-generation drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy.

Topics: Aminoquinolines; Aniline Compounds; Cell Line; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Indoles; Kinetics; Morpholines; Mutation; Naphthalenes; Neoplasms; Oncogene Proteins v-abl; Organic Chemicals; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyrazoles; Pyrroles; Sunitinib