A comprehensive review of imatinib mesylate (Gleevec) for dermatological diseases

Imatinib mesylate (Gleevec, also known as STI-571), is an approved oral treatment for patients with chronic myeloid leukemia (CML). It blocks the activity of Abelson cytoplasmic tyrosine kinase (ABL), c-Kit and the platelet-derived growth factor receptor (PDGFR). As an inhibitor of PDGFR, imatinib mesylate appears to have utility in the treatment of a variety of dermatological diseases. Imatinib has been reported to be an effective treatment for FIP1L1-PDGFRalpha+ mast cell disease, hypereosinophilic syndrome, and dermatofibrosarcoma protuberans. One report notes its effectiveness for treating HIV related Kaposi's sarcoma; imatinib has not been effective for the treatment of melanoma.     

Imatinib mesylate in a patient with metastatic disease originating from a dermatofibrosarcoma protuberans of the scalp

Dermatofibrosarcoma protuberans is a soft-tissue tumor that may recur locally and rarely causes metastases to vital organs. Dermatofibrosarcoma protuberans has specific chromosomal abnormalities involving the platelet-derived growth factor beta-chain locus that may render these tumors responsive to targeted therapy with the tyrosine kinase inhibitor imatinib mesylate. A patient with locally recurrent and metastatic dermatofibrosarcoma protuberans who had already undergone surgery 22 times was initially treated with imatinib mesylate 400 mg/day. The treatment dose was increased after 7 days to 400 mg twice daily. The patient was followed up for response and toxicity by physical examination and imaging studies, comprising computed tomography and fluorodeoxyglucose positron emission tomography. Clinical response could be demonstrated after the first month of treatment, and subsequent computed tomography and positron emission tomography documented a response to imatinib mesylate therapy. Our patient is now in sustained remission with minimal toxicity. We conclude that antitumor activity of metastatic dermatofibrosarcoma protuberans can be obtained with imatinib mesylate treatment with minimal side-effects.     

Biochemical and cellular effects of c-Src kinase-selective pyrido[2, 3-d]pyrimidine tyrosine kinase inhibitors

Increased expression or activity of c-Src tyrosine kinase has been associated with the transformed phenotype in tumor cells and with progression of neoplastic disease. A number of pyrido[2, 3-d]pyrimidines have been characterized biochemically and in cells as part of an assessment of their potential as anti-tumor agents. The compounds were ATP-competitive inhibitors of c-Src kinase with IC(50) values < 10 nM and from 6 to >100-fold selectivity for c-Src tyrosine kinase relative to basic fibroblast growth factor receptor (bFGFr) tyrosine kinase, platelet-derived growth factor receptor (PDGFr) tyrosine kinase, and epidermal growth factor receptor (EGFr) tyrosine kinase. The compounds yielded IC(50) values < 5 nM against Lck. Human colon tumor cell growth in culture was inhibited, as was colony formation in soft agar at concentrations < 1 microM. Phosphorylation of the c-Src cellular substrates paxillin, p130(cas), and Stat3 was also inhibited at concentrations < 1 microM. Autophosphorylation of EGFr tyrosine kinase or PDGFr tyrosine kinase was not inhibited by c-Src inhibitors, thus showing the selective nature of the compounds in cells. In a mitogenesis assay measuring thymidine incorporation stimulated by specific mitogens, the c-Src tyrosine kinase inhibitors reduced incorporated thymidine in a manner consistent with previously reported roles of c-Src in mitogenic signaling. Progression through the cell cycle was inhibited at G(2)/M in human colon tumor cells treated with two of the c-Src-selective compounds, which is also consistent with earlier reports describing a requirement for active c-Src tyrosine kinase for G(2) to M phase progression. The compounds described here are selective inhibitors of c-Src tyrosine kinase and have antiproliferative effects in tumor cells consistent with inhibition of c-Src.     

Cardiovascular & Renal: AT2 antagonist inhibition of vascular restenosis

Competition in the field of tyrosine kinase inhibitors has increased in the last few years. New receptor and non-receptor tyrosine kinases have been identified as attractive targets for drug discovery programs. A pharmacophore model of the ATP-binding site of the epidermal growth factor-receptor (EGF-R) tyrosine kinase has been developed and successfully used for the rational design of tyrosine kinase inhibitors. Several inhibitor classes containing a phenylamino-pyrimidine moiety in their structure have provided highly selective ATP-competitive tyrosine kinase inhibitors, active in the low nanomolar or even picomolar range, thus proving that the ATP-binding site of tyrosine kinases is an attractive target for the design of anticancer drugs. More and more examples of inhibitors against several tyrosine kinases are being described which, in addition to showing potent and selective in vitro<> activity, exhibit potency in relevant cellular and in vivo models.<> Presently, several tyrosine kinase inhibitors with an interesting in vitro and in vivo profile are in preclinical evaluation and are expected to enter Phase I clinical trials later this year or early next year. This review summarises development of the last two years in the design and biological profiling of tyrosine kinase inhibitors with special focus on the phenylamino-pyrimidine-containing classes of compounds.     

Developing target therapy against oncogenic tyrosine kinase in myeloid maliganacies

Myeloid malignancies are frequently associated with translocations and mutations of tyrosine kinase genes. Fusion genes involving ABL, ARG, PDGFRs, JAK2, SYK, TRKC, and FGFRs, and gain-of-function mutations of FLT3, KIT and JAK2 have been detected at various rates in myeloproliferative disease and acute myeloid leukemia. Furthermore, abnormal overexpression of tyrosine kinases such as FLT3 has also been reported. These gene products are constitutively activated and potentially transform hematopoietic cells by augmentation of proliferation and enhanced viability. Since the fusion or mutation of tyrosine kinase is a primary and central event in chronic myeloproliferative diseases, targeting the kinase activity has been thought to be an ideal intervention to treat these diseases. The clinical success of imatinib for chronic myeloid leukemia has made this idea a reality, and has accelerated the development of new tyrosine kinase inhibitors (TKIs). Challenging studies with TKIs have also been reported for acute myeloid leukemia. This review will focus on recent trials of TKIs against oncogenic tyrosine kinases (ABL, PDGFRs, FLT3 and KIT) in myeloid malignancies.     

An unusual case of capecitabine hyperpigmentation: Is hyperpigmentation a part of hand-foot syndrome or a separate entity?

A 59-year-old man with adenocarcinoma of stomach was prescribed capecitabine as adjuvant chemotherapy. After two cycles of therapy, patient developed hyperpigmentation on hands and feet. Examination revealed a peculiar distribution of hyperpigmentation on hands and feet and in addition, hyperpigmented spots on the dorsum of tongue. Although hand-foot syndrome (HFS) to capecitabine solely manifesting as palmoplantar hyperpigmentation has been described earlier, this is probably the first instance wherein oral pigmentation has also been found in association. In addition, this finding lends support to the growing argument of hyperpigmentation being a separate entity: different from HFS, both therefore being separate adverse effects of the same drug.     

Identification of Type‐II Inhibitors Using Kinase Structures

Spleen tyrosine kinase is a non‐receptor tyrosine kinase, overactivation of which is thought to contribute to autoimmune diseases as well as allergy and asthma. Protein kinases have a highly conserved ATP binding site, thus making challenging the design of selective small molecule inhibitors. It has been well documented that some protein kinases can be stabilized in their inactive conformations (Type‐II inhibitors). Herein, we describe a protein structure/ligand‐based approach to successfully identify ligands that bind to novel conformations of spleen tyrosine kinase. By utilizing kinase protein crystal structures both in the public domain (RCSB) and within Pfizer’s protein crystal database, we report the discovery of the first spleen tyrosine kinase Type‐II ligands. Compounds 1 and 3 were found to bind to the DFG‐out conformation of spleen tyrosine kinase, while compound 2 binds to a DFG‐in, C‐Helix‐out conformation. In this instance, the C‐helix moved significantly to create a large hydrophobic pocket rarely seen in kinase protein crystal structures.     

New assignments for multitasking signal transduction inhibitors

An article presented in this issue of Molecular Pharmacology (p. 1527) provides an intriguing example of how tyrosine kinase inhibitors can be put to many uses. In this article, the action of dasatinib (BMS-354825) is contrasted with that of imatinib, a kinase inhibitor that is currently being used to treat chronic myelogenous leukemia and other disorders. Both pharmacologic inhibitors target several tyrosine kinases, including Bcr-Abl and the platelet-derived growth factor receptor (PDGFR). Up to this point, the PDGFR has not been a primary therapeutic target for this class of agents. The work of Chen and colleagues shows that dasatinib is a particularly potent inhibitor of PDGFR and that the compound also targets Src kinase. The authors suggest that this combination of activities could be useful in the treatment of vascular obstructive diseases. Although a lack of absolute specificity has typically been regarded as a pharmacologic drawback, this study exemplifies how drugs with multiple molecular targets can potentially provide a very beneficial spectrum of therapeutic activities in multiple disease states.     

Tyrosine kinase inhibitors in cancer treatment (Part II)

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.     

Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases.

We have previously described a novel series of low molecular weight protein tyrosine kinase inhibitors which we named tyrphostins. The characteristic active pharmacophore of these compounds was the hydroxy-cis-benzylidenemalononitrile moiety. In this article we describe three novel groups of tyrphostins: (i) one group has the phenolic moiety of the cis-benzylidenemalononitrile replaced either with other substituted benzenes or with heteroaromatic rings, (ii) another is a series of conformationally constrained derivatives of hydroxy-cis-benzylidenemalononitriles in which the malononitrile moiety is fixed relative to the aromatic ring, and (iii) two groups of compounds in which the position trans to the benzenemalononitrile has been substituted by ketones and amides. Among the novel tyrphostins examined we found inhibitors which discriminate between the highly homologous EGF receptor kinase (HER1) and ErbB2/neu kinase (HER2). These findings may lead to selective tyrosine kinase blockers for the treatment of diseases in which ErbB2/neu is involved.     

Nilotinib therapy in chronic myelogenous leukemia

Imatinib mesylate (Gleevec; Novartis, Basel, Switzerland) is a highly effective inhibitor of the deregulated kinase activity of BCR-ABL in chronic myelogenous leukemia (CML) and represents the current standard of care for patients with this disease. Mutations within the ABL kinase domain that interfere with drug binding have been identified as the main mechanism of resistance to imatinib. Currently, more than 50 different BCR-ABL mutants conferring varying degrees of resistance to tyrosine kinase inhibitors have been identified. Nilotinib (Tasigna; Novartis) is a second-generation tyrosine kinase inhibitor with 30-fold higher potency against BCR-ABL kinase than imatinib. Notably, nilotinib is active against a wide range of imatinib-resistant or-intolerant patients, except for T315I. Results from the pivotal phase II studies of nilotinib for patients with CML after failure or intolerance to imatinib therapy indicate that nilotinib has a favorable toxicity profile and is highly efficacious in this setting. Studies exploring the efficacy of nilotinib as front-line therapy for patients with newly diagnosed CML are ongoing. Here, we review the preclinical and clinical development of nilotinib for the treatment of CML.     

Oridonin inhibited the tyrosine kinase activity and induced apoptosis in human epidermoid carcinoma A431 cells

Oridonin, an active component isolated from the plant Rabdosia rubescens, has been reported to exhibit antitumor effects, but little is known about its molecular mechanism of action. In this study, we first investigated the mechanism involved in oridonin-induced cell death in human epidermoid carcinoma A431 cells, which overexpress epidermal growth factor receptor (EGFR). After treatment with various doses of oridonin for 24 h, the majority of A431 cells underwent apoptosis in a time- and dose-dependent manner as measured by an LDH activity-based assay. Treatment with oridonin at various concentrations for 24 h caused significant inhibition on the total tyrosine kinase activities and downregulation of EGFR expression or EGFR phosphorylation. Oridonin significantly affected the localization of EGFR and phosphorylated EGFR on the cell membrane. However, genistein (a well-known tyrosine kinase inhibitor) did not induce apoptotic A431 cell death. Importantly, oridonin exhibited much stronger inhibitory effect on the total tyrosine kinase activities or EGFR tyrosine phosphorylation as well as much stronger suppression on EGFR and phosphorylated EGFR localization than genistein in A431 cells. Taken together, oridonin exerted a potential inhibitory effect on the tyrosine kinase activity of A431 cells. The decrease in the tyrosine kinase activity and the blockage of EGFR tyrosine phosphorylation might be one of the causes of oridonin-induced A431 cell death.     

Discovery of novel Bruton's tyrosine kinase inhibitors using a hybrid protocol of virtual screening approaches based on SVM model, pharmacophore and molecular docking

Bruton's tyrosine kinase has emerged as a potential target for the treatment for B-cell malignancies and autoimmune diseases. Discovery of Bruton's tyrosine kinase inhibitors has thus attracted much attention recently. In this investigation, we introduced a hybrid protocol of virtual screening methods including support vector machine model-based virtual screening, pharmacophore model-based virtual screening and docking-based virtual screening for retrieving new Bruton's tyrosine kinase inhibitors from commercially available chemical databases. Performances of the hybrid virtual screening approach were evaluated against a test set, which results showed that the hybrid virtual screening approach significantly shortened the overall screening time, and considerably increased the hit rate and enrichment factor compared with the individual method (SB-VS, PB-VS and DB-VS) or their combinations by twos. This hybrid virtual screening approach was then applied to screen several chemical databases including Specs (202,408 compounds) and Enamine (980,000 compounds) databases. Thirty-nine compounds were selected from the final hits and have been shifted to experimental studies.     

Omacetaxine mepesuccinate for the treatment of leukemia

Introduction: Omacetaxine mepesuccinate, formerly known as homoharringtonine, is a first-in-class cephalotaxine that has experienced phases of increasing and waning interest since its first use in traditional Chinese medicine. With activity being reported in patients with chronic myeloid leukemia (CML) resistant to currently available tyrosine kinase inhibitors, renewed interest has recently been generated.

Areas covered: The development of omacetaxine mepesuccinate, with emphasis on synthesis and mode of administration, is addressed. An overview on current clinical results as a single agent or within combination regimens in patients with acute myeloid leukemia (AML) and CML is given.

Expert opinion: Omacetaxine mepesuccinate has a unique mode of action and appreciable activity in AML and CML with generally mild nonhematologic toxicity. In patients with AML, results indicate a role within combination regimens in selected, possibly elderly patient populations. In CML, patients with resistance to tyrosine kinase inhibitors, especially due to the T315I mutation, are the most intensively studied. Despite successful results in some patients, single-agent therapy with omacetaxine mepesuccinate has resulted in modest results. However, upfront combination with tyrosine kinase inhibitor represents an attractive option due their differing mechanisms of action.     

Blockade of vascular endothelial growth factor receptor signal pathway and antitumor activity of ON-III (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone), a component from Chinese herbal medicine

Antiangiogenesis is a promising strategy of cancer treatment. Vascular endothelial growth factor receptor [fetal liver kinase/kinase-inserting domain-containing receptor (KDR)] is a tyrosine kinase receptor and has been strongly implicated in tumor angiogenesis. In this study, we report that 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (ON-III), extracted from the dried flower Cleistocalyx operculatus, used in traditional Chinese medicine, reversibly inhibited KDR tyrosine kinase phosphorylation, but epidermal growth factor receptor tyrosine kinase phosphorylation was unaffected under the same concentrations of ON-III. ON-III also inhibited mitogen-activated protein kinase (MAPK) and AKT activation of KDR signal transduction in downstream molecules without reduced total MAPK and AKT. The results in vitro showed that ON-III inhibited growth of human vascular endothelial HDMEC cells in the presence of VEGF preferentially, compared with epidermal growth factor. Systemic administration of ON-III at nontoxic doses in nude mice resulted in inhibition of subcutaneous tumor growth of human hepatocarcinoma Bel7402 and lung cancer GLC-82 xenografts. The tumor vessel density decreased, as determined by immunohistochemical staining, for CD31 after ON-III treatment. These results indicated that ON-III inhibited KDR tyrosine kinase, shut down KDR-mediated signal transduction, and inhibited tumor growth of human xenografts in vivo.     

Tyrosine kinases as targets in cancer therapy - successes and failures

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.     

Tyrosine kinases as targets in cancer therapy – successes and failures

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.     

Receptor tyrosine kinases: the main targets for new anticancer therapy

Because conventional chemotherapy is not specific for cancer cells leading to toxic side effects there is a need for novel agents with high grade antitumor specificity. The major prerequisite to develop such drugs is to understand the targets that these agents should attack. In recent years a number of promising new anticancer drugs have been developed which target intracellular pathways or extracellular cell molecules. The clinically most effective compounds function as tyrosine kinase inhibitors. In the past, various tyrosine kinase receptors have been identified as regulators of tumor or tumor vessel growth. Having shown their expression characteristics in different tumor entities, specific inhibitors of the ATP binding sites of these receptors or antibodies were developed and entered clinical trials. The pathognomonic role of the tyrosine kinase defines the way of action of the inhibiting drug, whereas the amount of expression in tumor tissue defines the rationale to use the inhibitor to treat a specific protein. The future will define indications for such drugs by tumor kinase profiles instead of tumor entities. Gleevec, inhibiting the BCR-ABL tyrosine kinase; Iressa, inhibiting the EGF-receptor tyrosine kinase; Herceptin, inhibiting the Her2/neu tyrosine kinase and PTK787/ZK222584, inhibiting the VEGF-receptor tyrosine kinase will be discussed as representatives of selective tyrosine kinase inhibitors whereas ZD6474 and SU6668 will be discussed as representatives of multitarget tyrosine kinase inhibitors.     

Involvement of tyrosine kinase pathway in acute hypoxic vasoconstriction in sheep isolated pulmonary vein

Tyrosine kinase pathway has been shown to be involved in the effects of hypoxia in pulmonary arteries, but its role in pulmonary vein is not known. The aims of this study were to determine the effect of hypoxia in sheep isolated pulmonary veins and to identify the role of tyrosine kinase pathway in hypoxic response. Genistein and tyrphostin were used as selective tyrosine kinase inhibitors, and sodium orthovanadate was administered for tyrosine kinase activation. Hypoxia (95% N(2) to 5% CO(2)) caused a vasoconstriction either under resting tone or in U46619-precontracted pulmonary veins. Genistein and tyrphostin inhibited hypoxia-induced vasoconstriction both under resting tone and in precontracted veins, while sodium orthovanadate increased these hypoxic contractions. Our findings suggest that tyrosine kinase pathway is involved in hypoxic pulmonary vasoconstriction in sheep isolated pulmonary vein rings.     

Imatinib mesylate,the first molecularly targeted gene suppressor

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, and drug-drug and drug-food interactions of imatinib and the economic considerations of imatinib in the treatment of chronic myeloid leukemia (CML). DATA SOURCES: Literature accessed through MEDLINE (January 1970-January 2002), abstracts from the 2001 annual meetings of the American Society of Clinical Oncology and the American Society of Hematology, imatinib product labeling, and additional studies or abstracts identified from the bibliographies of the reviewed literature were used to compile data. Key search terms were allogeneic bone marrow transplant and stem cell transplant, chronic myeloid leukemia, imatinib, interferon, Gleevec, leukemia, gastrointestinal stromal tumors, STI-571, and tyrosine kinase inhibitors. FINDINGS: Imatinib is a distinctively characteristic drug targeted toward inhibition of tyrosine kinase activity. Imatinib is indicated for the treatment of patients with CML who failed interferon (IFN)-alpha therapy and for the treatment of patients with gastrointestinal stromal tumors (GISTs) expressing the tyrosine kinase receptor c-kit. Imatinib produces positive short-term hematologic and cytogenetic responses in patients with CML; short-term positive objective responses have been shown for patients with GISTs. To our knowledge, there are no controlled trials demonstrating long-term safety, improvement in disease-related symptoms, or increased survival with imatinib. Serious adverse effects requiring dosage decreases and/or therapy termination are edema, hepatotoxicity, and hematologic toxicity. Imatinib also has been found to inhibit tyrosine kinases involved in the growth of other malignancies. The role of imatinib in tumors that express a tyrosine kinase is constantly evolving with new research results. CONCLUSIONS: Imatinib therapy should be limited to patients whose tumor growth is related to a genetically defective tyrosine kinase. In cases of CML, imatinib should be further limited to patients who have tried and failed IFN-alpha therapy or who are not candidates for an allogeneic stem cell transplant.