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1.
Over the past 5 years, small molecule tyrosine kinase inhibitors have been successfully introduced as new cancer therapeutics. The pioneering work with the ABL inhibitor imatinib (Glivec, Gleevec) was rapidly extended to other types of leukemias as well as solid tumors, which stimulated the development of a variety of new tyrosine kinase inhibitors. Unfortunately, oncogenic tyrosine kinases seem to have little problem to develop resistance to these inhibitors, and there is good evidence that this is not limited to imatinib, but also occurs with other inhibitors, such as FLT3 and EGFR inhibitors. Based on studies with imatinib, mutation and amplification of the target kinase seem to be the most important mechanisms for the development of resistance, but these mechanisms alone cannot explain all cases of resistance. A better understanding of the resistance mechanisms will be required to design improved treatment strategies in the future. In this review, we summarize the current insights in the different mechanisms of resistance to small molecule tyrosine kinase inhibitors, and discuss future improvements that might limit or even overcome resistance. 相似文献
2.
Mechanisms of resistance to imatinib in CML patients: a paradigm for the advantages and pitfalls of molecularly targeted therapy 总被引:1,自引:0,他引:1
One of the challenges of cancer therapeutics is to discover targets unique to the tumor cell population. Constitutively activated tyrosine kinases play a role in the malignant phenotype in a number of different cancers. While the kinases may be present in the normal cell, the cancer cell is often dependent upon the activation of the kinase for the maintenance of malignant growth. Inhibition of kinase activation may therefore selectively inhibit malignant proliferation. In the case of chronic myelogenous leukemia (CML), the activated tyrosine kinase (BCR-ABL) is due to a chromosomal translocation that defines this disease, and is necessary for malignant transformation. Imatinib mesylate (Gleevec, Novartis) is a small molecule tyrosine kinase inhibitor, developed through the chemical modification to be selected for a small number of tyrosine kinases present in human cells. This agent is also orally bioavailable and has been found to be effective in clinical trials. We have learned much through the clinical use of this agent. 1) Specific targeting of activated signal transduction pathways may be effective in inhibiting cancer cells. 2) Cancer cells may not only be inherently resistant to small molecule inhibitors, but may also develop resistance after exposure to the inhibitor. 3) Increased knowledge regarding critical signal transduction pathways, the structure of the molecules that are being targeted and the inhibitors themselves, will allow us to understand resistance as it develops and create new molecules to bypass resistance. We will discuss imatinib as an important example of the success and pitfalls of targeted therapeutics for cancer. 相似文献
3.
Traxler P 《Expert opinion on therapeutic targets》2003,7(2):215-234
Protein kinases play a crucial role in signal transduction and also in cellular proliferation, differentiation and various regulatory mechanisms. The inhibition of growth-related kinases, especially tyrosine kinases, might therefore provide new therapies for diseases such as cancer. Due to the enormous progress that has been made in the past few years in the identification of the human genome, in molecular and cell biology technologies, in structural biology and in bioinformatics, the number of receptor and non-receptor tyrosine kinases that have been identified as valuable molecular targets has greatly increased. Currently, more than 20 different tyrosine kinase targets are under evaluation in drug discovery projects in oncology. The progress made in the crystallisation of protein kinases, in most cases complexed with ATP-site-directed inhibitors, has confirmed that the ATPbinding domain of tyrosine kinases is an attractive target for rational drug design; more than 20 ATP-competitive, low molecular weight inhibitors are in various phases of clinical evaluation. Meanwhile, clinical proof-of-concept (POC) has been achieved with several antibodies and small molecules targeted against tyrosine kinases. With Herceptin, Glivec and Iressa (registered in Japan), the first kinase drugs have entered the market. This review describes the preclinical and clinical status of low molecular weight drugs targeted against different tyrosine kinases (e.g., epidermal growth factor receptor [EGFR], vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Kit, Fms-like tyrosine kinase [Flt]-3), briefly describes new targets, and provides a critical analysis of the current situation in the area of tyrosine kinase inhibitors. 相似文献
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5.
Numerous small molecule synthetic tyrosine kinase inhibitors are in clinical development for the treatment of human cancers. These fall into three broad categories: inhibitors of the epidermal growth factor receptor tyrosine kinase family (e.g., Iressa trade mark and Tarceva trade mark ), inhibitors of the split kinase domain receptor tyrosine kinase subgroup (e.g., PTK787/ZK 222584 and SU11248) and inhibitors of tyrosine kinases from multiple subgroups (e.g., Gleevec trade mark ). In addition, agents targeting other tyrosine kinases implicated in cancer, such as Met, Tie-2 and Src, are in preclinical development. As experience is gained in the clinic, it has become clear that unleashing the full therapeutic potential of tyrosine kinase inhibitors will require patient preselection, better assays to guide dose selection, knowledge of mechanism-based side effects and ways to predict and overcome drug resistance. 相似文献
6.
《Expert opinion on therapeutic patents》2013,23(12):1599-1625
In the last few years, enormous progress in the field of signal transduction inhibition has been made. Many companies have entered the field. Along with the epidermal growth factor receptor (EGFR) tyrosine kinase, many other tyrosine kinases have been identified as interesting targets for drug discovery projects. X-ray data of more than 40 crystal structures of protein kinases, in most cases complexed with an inhibitor, have been published. Pharmacophore models for the binding of inhibitors in the ATP-binding site of protein kinases have been developed that are generally applicable, enabling the rational design of tyrosine as well as serine/threonine kinase inhibitors. It has been proven by numerous examples that the ATP-binding of protein kinases is an exciting target for the design of anticancer drugs. In many cases, it has also been demonstrated that through rational design it is possible to modify a lead structure in such a way that inhibitors with an altered selectivity profile are obtained. Chemical optimisation of several lead structures led to development candidates with potent in vitro and in vivo activity fulfilling the pharmacodynamic, pharmacokinetic, toxicological and technical (synthesis, formulation) requirements for a clinical candidate. Currently, there are seven tyrosine kinase inhibitors in early phases of clinical trials. In addition, several candidates are close to entering Phase I trials this year or at the beginning of next year. It is expected that positive results from clinical trials will greatly contribute to the clinical proof of concept of the value of signal transduction inhibition and will greatly stimulate further research in this area. This review is a continuation of a review with the same title of last year and summarises published patent literature and related publications between 1997 and September 1998. 相似文献
7.
Sathornsumetee S 《Anti-cancer agents in medicinal chemistry》2011,11(8):700-711
Glioblastoma (GBM), the most common primary brain tumor in adults, is one of the most aggressive human cancers associated with high mortality. Standard treatments following diagnosis include surgical resection, radiotherapy and adjunctive chemotherapy. However, almost all patients develop disease progression following this multimodal therapy. Recent understanding in genomic and molecular abnormalities in GBM has shifted the treatment paradigm towards using molecularly targeted agents. One of the most prominent targets in cancer treatment is kinases, which can be commonly targeted by small molecule inhibitors or monoclonal antibodies. Despite the initial enthusiasm in exploring kinase inhibitors for GBM, first-generation kinase inhibitors that selectively disrupt single kinases have failed to demonstrate clinical benefit in most patients with GBM. Mechanisms of resistance may include genetic heterogeneity with cross-talk and coactivation of multiple signaling pathways, upregulation of alternative signaling cascades, limited drug delivery and existence of highly-resistant cellular subpopulations such as cancer stem cells. One strategy to circumvent this challenge is to target multiple kinases by multitargeted kinase inhibitors or combinations of single targeted kinase inhibitors, both of which have been evaluated in clinical trials for GBM. 相似文献
8.
《Expert opinion on investigational drugs》2013,22(1):51-64
Numerous small molecule synthetic tyrosine kinase inhibitors are in clinical development for the treatment of human cancers. These fall into three broad categories: inhibitors of the epidermal growth factor receptor tyrosine kinase family (e.g., Iressa? and Tarceva?), inhibitors of the split kinase domain receptor tyrosine kinase subgroup (e.g., PTK787/ZK 222584 and SU11248) and inhibitors of tyrosine kinases from multiple subgroups (e.g., Gleevec?). In addition, agents targeting other tyrosine kinases implicated in cancer, such as Met, Tie-2 and Src, are in preclinical development. As experience is gained in the clinic, it has become clear that unleashing the full therapeutic potential of tyrosine kinase inhibitors will require patient preselection, better assays to guide dose selection, knowledge of mechanism-based side effects and ways to predict and overcome drug resistance. 相似文献
9.
One promising therapeutic strategy for treating cancer is to specifically target signal transduction pathways that have a key role in oncogenic transformation and malignant progression. Hsp90 is an emerging therapeutic target of interest for the treatment of cancer. It is responsible for modulating cellular response to stress by maintaining the function of numerous signalling proteins - known as 'client proteins' - that are associated with cancer cell survival and proliferation. Many cancers result from specific mutations in, or aberrant expression of, these client proteins. Small molecule Hsp90 inhibitors bind to the ATP binding pocket, inhibit chaperone function and could potentially result in cytostasis or cell death. Consequently, many client proteins are targeted for degradation via the ubiquitin-proteasome pathway including receptor and non receptor kinases (Erb-B2, epidermal growth factor receptor, and Src family kinases), serine/threonine kinases (c-Raf-1 and Cdk4), steroid hormone receptors (androgen and estrogen), and apoptosis regulators such as mutant p53. Inhibition of Hsp90 function has also proven effective in killing cancer cells that have developed resistance to targeted therapies such as kinase inhibitors. This review is intended to update recent developments in new Hsp90 inhibitors as antitumors agents, the design, biological evaluation and their clinical trials studies. 相似文献
10.
Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents 总被引:13,自引:0,他引:13
Abnormal cell signal transduction arising from protein tyrosine kinases has been implicated in the initiation and progression of a variety of human cancers. Over the past 2 decades pharmaceutical and university laboratories have been involved in a tremendous effort to develop compounds that can selectively modulate these abnormal signalling pathways. Targeting receptor tyrosine kinases, especially the epidermal growth factor receptor subfamily, has been at the forefront of this effort as a result of strong clinical data correlating over-expression of these receptors with more aggressive cancers. There are a variety of strategies under development for inhibiting the kinase activity of these receptors, targeting both the extracellular and intracellular domains. Antibody-based approaches, immunotoxins and ligand-binding cytotoxic agents use the extracellular domain for targeted tumour therapy. Small molecule inhibitors target the intracellular catalytic region by interfering with ATP binding, while nonphosphorylatable peptides are aimed at the intracellular substrate binding region. Compounds that inhibit subsequent downstream signals from the receptor by interrupting intracellular protein recognition sequences are also being investigated. In the past 5 years enormous progress has been made in developing tyrosine kinase inhibitor compounds with sufficient potency, bioavailability and selectivity against this subfamily of receptor tyrosine kinases. The anti-HER2 monoclonal antibody, trastuzumab, for patients with metastatic breast cancer is the first of these inhibitor compounds to gain FDA approval. However, preclinical and clinical trials are ongoing with a variety of other monoclonal antibodies, immunotoxins, and small molecule quinazoline and pyrimidine-based inhibitors. Although their cytotoxic and cytostatic potential has been proven, they are not likely to replace standard chemotherapy regimens as single-agent, first-line therapeutics. Instead, their promising additive and synergistic antitumour effects in combination with standard chemotherapeutics suggest that these novel agents will find their greatest utility and efficacy in conjunction with existing anticancer agents. 相似文献
11.
Many new targeted small molecule anticancer kinase inhibitors are actively being developed. However, the clinical use of some kinase inhibitors has been shown to result in cardiotoxicity. In most cases the mechanisms by which they exert their cardiotoxicity are not well understood. We have used large scale profiling data on 8 FDA-approved tyrosine kinase inhibitors and 10 other kinase inhibitors to a panel of 317 kinases in order to correlate binding constants and kinase inhibitor binding selectivity scores with kinase inhibitor-induced damage to neonatal rat cardiac myocytes. The 18 kinase inhibitors that were the subject of this study were: canertinib, dasatinib, dovitinib, erlotinib, flavopiridol, gefitinib, imatinib, lapatinib, midostaurin, motesanib, pazopanib, sorafenib, staurosporine, sunitinib, tandutinib, tozasertib, vandetanib and vatalanib. The combined tyrosine kinase and serine-threonine kinase selectivity scores were highly correlated with the myocyte-damaging effects of the kinase inhibitors. This result suggests that myocyte damage was due to a lack of target selectivity to binding of both tyrosine kinases and serine-threonine kinases, and was not due to binding to either group specifically. Finally, the strength of kinase inhibitor binding for 290 kinases was examined for correlations with myocyte damage. Kinase inhibitor binding was significantly correlated with myocyte damage for 12 kinases. Thus, myocyte damage may be multifactorial in nature with the inhibition of a number of kinases involved in producing kinase inhibitor-induced myocyte damage. 相似文献
12.
The pp60c‐Src is one of the ubiquitously expressed Src family kinases and has important functions in malignant cells, including regulation of cell division, growth factor signaling, and movement. Therefore, investigating new small molecule inhibitors of pp60c‐Src is important to discover and develop novel therapeutics for cancer and metastasis. Moreover, some of the small molecule inhibitors that do not qualify for therapeutic use may become very useful tool to explore the role of Src kinase in normal cells as well as in a variety of disease models. Our continuous efforts to find novel inhibitors of pp60c‐Src aimed for therapeutic and research use, we synthesized newly designed aminomethylindole derivatives as novel small molecule inhibitors and investigated their inhibitory effect on pp60c‐Src tyrosine kinase. Here, we report one potential inhibitor of the pp60c‐Src from five active molecules of all nine compounds, which were synthesized and screened for the biological activity of the molecules against pp60c‐Src target. 相似文献
13.
Swords R Kelly K Carew J Nawrocki S Mahalingam D Sarantopoulos J Bearss D Giles F 《Current drug targets》2011,12(14):2059-2066
The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to cancer development and progression. They were first recognized as pro-viral integration sites for the Moloney Murine Leukemia virus. Unlike other kinases, they possess a hinge region which creates a unique binding pocket for ATP. Absence of a regulatory domain means that these proteins are constitutively active once transcribed. Pim kinases are critical downstream effectors of the ABL (ableson), JAK2 (janus kinase 2), and Flt-3 (FMS related tyrosine kinase 1) oncogenes and are required by them to drive tumorigenesis. Recent investigations have established that the Pim kinases function as effective inhibitors of apoptosis and when overexpressed, produce resistance to the mTOR (mammalian target of rapamycin) inhibitor, rapamycin . Overexpression of the PIM kinases has been reported in several hematological and solid tumors (PIM 1), myeloma, lymphoma, leukemia (PIM 2) and adenocarcinomas (PIM 3). As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Novel small molecule inhibitors of the human Pim kinases have been designed and are currently undergoing preclinical evaluation. 相似文献
14.
FMS-like tyrosine kinase-3 (FLT3) is a tyrosine kinase receptor involved in the survival and expansion of hematopoietic stem progenitors. A constitutively activated, mutated form of FLT3, is expressed in approximately 30% of de novo acute myeloid leukemia (AML) and about 6% of acute lymphoblastic leukemia (ALL) cases. Since mutant FLT3 has emerged as an attractive therapeutic target, there are several FLT3 inhibitors currently undergoing evaluation in different phases of clinical trials. However, although many aspects of the intracellular signaling mediated by oncogenic FLT3 have been revealed, what is the best strategy to inhibit FLT3 and how FLT3 inhibitors should be developed for AML treatment is poorly defined. Despite promising in vitro studies, where most FLT3 inhibitors show potent efficacy at nanomolar concentrations, clinical responses in AML patients are moderate and temporary. Furthermore, under prolonged therapy, FLT3 mutation-positive leukemic cells rapidly develop resistance to FLT3 inhibitors when used as monotherapy. Considering that there is no uniform mechanism of resistance triggered by FLT3 inhibitors, it will be necessary to develop new agents that target FLT3, and that can be used consecutively or in combination with conventional cytotoxic therapeutics. On the other hand, given that overexpression of FLT3 ligand (FL), occurring after myelosuppressive therapy, reduces the efficacy of FLT3 inhibitors, targeting both FL and FLT3 kinase, might be more effective approach in AML treatment. Here, we summarize up-to-date studies on FLT3 structure, its mutation status and role in malignant signal trafficking. We also review why FLT3 targeted therapies have not revolutionized AML treatment. 相似文献
15.
Meulenbeld HJ Mathijssen RH Verweij J de Wit R de Jonge MJ 《Expert opinion on investigational drugs》2012,21(3):383-393
INTRODUCTION: Drugs that interfere with the normal progression of mitosis belong to the most successful cytotoxic agents currently used for anticancer treatment. Aurora kinases are serine/threonine kinases that function as key regulators of mitosis and are frequently overexpressed in human cancers. The use of several small molecule aurora kinase inhibitors as potential anticancer therapeutic is being investigated. Danusertib (formerly PHA-739358) is a small ATP competitive molecule that inhibits aurora A, B and C kinases. Interestingly, danusertib also inhibits several receptor tyrosine kinases such as Abl, Ret, FGFR-1 and TrkA. These tyrosine kinases are involved in the pathogenesis of a variety of malignancies and the observed multi-target inhibition may increase the antitumor activity resulting in extending the indication. Danusertib was one of the first aurora kinase inhibitors to enter the clinic and has been studied in Phase I and II trials. AREAS COVERED: This review provides an updated summary of preclinical and clinical experience with danusertib up to July 2011. EXPERT OPINION: Future studies with danusertib should focus on the possibility of combining this agent with other targeted anticancer agents, chemotherapy or radiotherapy. As a single agent, danusertib may show more promise in the treatment of leukemias than in solid tumors. 相似文献
16.
17.
《Expert opinion on therapeutic targets》2013,17(2):215-234
Protein kinases play a crucial role in signal transduction and also in cellular proliferation, differentiation and various regulatory mechanisms. The inhibition of growth-related kinases, especially tyrosine kinases, might therefore provide new therapies for diseases such as cancer. Due to the enormous progress that has been made in the past few years in the identification of the human genome, in molecular and cell biology technologies, in structural biology and in bioinformatics, the number of receptor and non-receptor tyrosine kinases that have been identified as valuable molecular targets has greatly increased. Currently, more than 20 different tyrosine kinase targets are under evaluation in drug discovery projects in oncology. The progress made in the crystallisation of protein kinases, in most cases complexed with ATP-site-directed inhibitors, has confirmed that the ATPbinding domain of tyrosine kinases is an attractive target for rational drug design; more than 20 ATP-competitive, low molecular weight inhibitors are in various phases of clinical evaluation. Meanwhile, clinical proof-of-concept (POC) has been achieved with several antibodies and small molecules targeted against tyrosine kinases. With Herceptin, Glivec and Iressa (registered in Japan), the first kinase drugs have entered the market. This review describes the preclinical and clinical status of low molecular weight drugs targeted against different tyrosine kinases (e.g., epidermal growth factor receptor [EGFR], vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Kit, Fms-like tyrosine kinase [Flt]-3), briefly describes new targets, and provides a critical analysis of the current situation in the area of tyrosine kinase inhibitors. 相似文献
18.
Cinzia Lanzi 《Biochemical pharmacology》2009,77(3):297-788
The limited efficacy of conventional treatments in progressive thyroid carcinomas indicates the need for new therapeutic options. Activating mutations of the receptor tyrosine kinase-encoding RET gene have been identified as driving oncogenic events in subsets of papillary (PTC) and medullary (MTC) thyroid carcinomas suggesting the interest of targeted therapy. The role of RET oncogenes and the encoded constitutively active oncoproteins as potential targets has been investigated by different strategies including gene therapy and pharmacological approaches, but targeted treatment for RET-driven cancers is not clinically available in current therapy. Small molecule tyrosine kinase inhibitors, including sorafenib, sunitinib, motesanib and vandetanib, which have already shown efficacy against other neoplastic diseases, are being evaluated in clinical trials for treatment of thyroid carcinomas. Most of them, also described as Ret inhibitors, are multi-kinase inhibitors with antiangiogenic activity related to inhibition of receptor tyrosine kinases, such as the vascular endothelial growth factor receptors. Preclinical evidence supports the relevance of Ret oncoproteins as therapeutic targets for a subset of thyroid neoplastic diseases and, although targeting the original causal genetic change may not be sufficient to control the disease efficiently, the available knowledge outlines therapeutic opportunities for exploiting Ret inhibition. 相似文献
19.
Hui Liu Weimin Qiu Tianyu Sun Lei Wang Chenxi Du Yanyu Hu Wenyuan Liu Feng Feng Yao Chen Haopeng Sun 《药学学报(英文版)》2022,12(4):1781-1804
Glioblastoma (GBM) is the most common aggressive malignant tumor in brain neuroepithelial tumors and remains incurable. A variety of treatment options are currently being explored to improve patient survival, including small molecule inhibitors, viral therapies, cancer vaccines, and monoclonal antibodies. Among them, the unique advantages of small molecule inhibitors have made them a focus of attention in the drug discovery of glioblastoma. Currently, the most used chemotherapeutic agents are small molecule inhibitors that target key dysregulated signaling pathways in glioblastoma, including receptor tyrosine kinase, PI3K/AKT/mTOR pathway, DNA damage response, TP53 and cell cycle inhibitors. This review analyzes the therapeutic benefit and clinical development of novel small molecule inhibitors discovered as promising anti-glioblastoma agents by the related targets of these major pathways. Meanwhile, the recent advances in temozolomide resistance and drug combination are also reviewed. In the last part, due to the constant clinical failure of targeted therapies, this paper reviewed the research progress of other therapeutic methods for glioblastoma, to provide patients and readers with a more comprehensive understanding of the treatment landscape of glioblastoma. 相似文献
20.
Tyrosine kinases, first described as oncogenes, have been shown to play a role in normal cellular processes. Aberrations in tyrosine kinase activity lead to disease states. For fifteen years it has been postulated that the inhibition of tyrosine kinases may have therapeutic utility and the design and testing of inhibitors have been major focuses of research and development in both academic institutions and pharmaceutical companies. While early research focused on developing chemical entities that mimic phosphotyrosine, later research has focused on developing competitive adenosine triphosphate (ATP) inhibitors with various levels of selectivity on kinase targets. This review focuses on a discussion of tyrosine kinases thought to be important in disease, including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial cell growth factor (VEGF), epidermal growth factor (EGF) receptors, HER-2 and Src. In addition, the classes of inhibitors designed to affect these targets and that have overcome research and development challenges and entered clinical trials are discussed. These include isoxazole, quinazoline, substituted pyrimidines and indolinone compounds, all of which are in clinical trials or near clinical development by SUGEN, Zeneca, Novartis, Pfizer and Parke-Davis. A summary of the chemistry and activity of these agents is provided. 相似文献