Inhibitors targeting hepatocyte growth factor receptor and their potential therapeutic applications

The hepatocyte growth factor (HGF)/c-Met signaling pathway is important in mediating a wide range of biological activities, including embryological development, wound healing, tissue regeneration, angiogenesis, proliferation, survival, scattering, motility, invasion and morphogenic differentiation. HGF and/or c-Met are expressed at abnormally high levels in a large variety of solid tumors. Various c-Met mutations have been described in many solid tumors and some hematologic malignancies. Therefore, inhibition of the HGF/c-Met signaling pathway has great potential in molecular targeted cancer therapy. Many patent applications associated with inhibition of the HGF/c-Met axis have been published in the past few years. There are four small molecule c-Met inhibitors presently in clinical trials. This review focusses on recent patent applications for small molecule c-Met inhibitors and their potential applications in cancer therapy.     

Optimization techniques for novel c-Met kinase inhibitors

Introduction: c-Met kinase plays an important part in the regulation of cell growth, invasion and anti-apoptosis. This enzyme is also an important target in cancer treatment. Through structural optimization and structure-activity studies of drugs currently on the market and those still in clinical trials, a great number of novel c-Met kinase inhibitors have been developed. This review focuses on recent developments in research regarding novel c-Met inhibitor synthesis, optimization, and structure-activity relationship (SAR) studies.

Area covered: In this review, the authors discuss the representative research of c-Met inhibitors published in recent years. Furthermore, it provides background research of c-Met kinase inhibitors, the introduction of drugs on the market and in clinical research, and the research progress of novel small molecule inhibitors. In particular, this review emphasizes the important role of ‘5-atoms linker’ in the design of some novel c-Met enzyme inhibitors.

Expert opinion: Discovering novel c-Met kinase inhibitors via natural product chemistry may become a new research field. Though it is difficult, the key to developing better c-Met kinase inhibitors is structural optimization.     

The role of HGF/c-Met signaling in prostate cancer progression and c-Met inhibitors in clinical trials

Introduction: An increasing number of basic, translational and clinical studies demonstrate the importance of the protein tyrosine kinase receptor, c-Met, in the progression of prostate cancer. c-Met is overexpressed in primary prostate cancers, further increased in expression in bone metastases and is associated with the development of castrate-resistant disease. Because of its importance as a target, c-Met inhibitors have reached clinical trial for advanced, castrate-resistant prostate cancer.

Areas covered: In this review, altered expression of c-Met and hepatocyte growth factor in prostate tumors and the microenvironment and how they contribute to growth and invasion of prostate cancer cells is described. Next, preclinical studies providing the support for use of c-Met inhibitors are discussed. Finally, early promising results from c-Met inhibitors in clinical trial, and future prospects for c-Met inhibitors in the treatment of advanced stage prostate cancer, are discussed.

Expert opinion: An emerging theme in treating metastatic prostate cancer is the requirement to target both the epithelial and stromal compartments. Results from clinical trials suggest that inhibitors of c-Met that block stromal-mediated c-Met activation in prostate tumors may be important therapeutic agents in at least a subset of patients with metastatic prostate cancer. However, as many of the inhibitors have multiple targets, the efficacy of targeting c-Met alone remains to be determined.     

Inhibitors targeting hepatocyte growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases

Amgen disclosed a series of 4-heteroaryloxy quinoline/quinazoline compounds as multiple kinase inhibitors, including hepatocyte growth factor (HGF) receptor tyrosine kinase c-Met and vascular endothelial growth factor (VEGF) receptor tyrosine kinase. These compounds are stated to have wide therapeutic applications for the treatment of a variety of cancers, hypertension, arteriosclerosis, myocardial infarction and rheumatoid arthritis.     

Investigational platelet-derived growth factor receptor kinase inhibitors in breast cancer therapy

Introduction: Aberrant regulation of platelet-derived growth factors (PDGFs) and their receptors (PDGFR) has been shown to be involved in many solid tumors, including breast cancer. PDGFR-α and PDGFR-β expressions were documented in breast cancer and are correlated with tumor aggressiveness and metastasis. Preclinical evidence further suggests tumor stimulatory roles of PDGFRs expressed by tumor stroma cells and indicates a deleterious effect of stromal PDGFRs on intratumoral drug uptake.

Areas covered: This review summarizes the present understanding of PDGF signaling in breast cancer based on experimental studies and available clinical trials. It also provides a critical discussion of selected ongoing clinical trials in patients with breast cancer involving PDGFR inhibition with tyrosine kinase inhibitors, specifically in endocrine responsive breast cancer.

Expert opinion: An increased molecular understanding of response and resistance mechanisms to endocrine therapy will be essential for therapeutic advances in PDGFR-directed cancer therapy. Future developments in the field will rely on clinical studies where prospective analyses of target expression in breast cancer cells and in the tumor stroma are included. More selective PDGFR inhibitors with reduced side effects will be crucial for combinatorial therapies. Development of sensitive diagnostics is of critical importance for patient selection and monitoring of therapeutic effects.     

Tyrosine kinase inhibitors in the treatment of prostate cancer: taking the next step in clinical development

Introduction: Prostate cancer (PCa) is the most frequently diagnosed, non-cutaneous malignancy in Western countries. Until recently, few therapeutic options were available for patients with advanced PCa. Although these treatments may delay progression of disease, none are curative. Therefore, research continues to investigate other treatments for advanced PCa. Tyrosine kinase inhibitors (TKIs) have been extensively studied as a treatment for multiple malignancies and may represent an additional strategy. In addition to limiting cellular proliferation and metastasis, there is also growing interest in using these treatments to impact the bone microenvironment and reduce associated morbidity from PCa.

Areas covered: Several TKIs have been evaluated in the preclinical setting in advanced PCa. Targets reviewed include the epidermal growth factor family, VEGF receptor, c-Src family kinases, platelet-derived growth factor and c-Met.

Expert opinion: Despite strong biological rationale for the use of TKIs therapy for the treatment of PCa, Phase III clinical trials have produced disappointing results. As TKI strategies move forward, the failures of past trials need to be better understood. New approaches with these treatments will also have to take into account modern anti-androgens and a treatment landscape that now includes immunotherapy.     

Investigational fibroblast growth factor receptor 2 antagonists in early phase clinical trials to treat solid tumors

ABSTRACT

Introduction: Fibroblast growth factor receptor 2 (FGFR2) is a highly conserved transmembrane tyrosine kinase receptor. FGFR2 dysregulation occurs in numerous human solid tumors and overexpression is closely associated with tumor progression. FGFR2 has recently been reported as a therapeutic target for cancer. Several targeted therapies are being investigated to disrupt FGFR2 activity; these include multi-target tyrosine kinase inhibitors (TKIs), pan-FGFR targeted TKIs and FGFR2 monoclonal antibodies.

Areas: This review examines FGFR2 regulation and function in cancer and its potential as a target for cancer treatment.

Expert opinion: Highly specific FGFR2 blockers have not yet been developed and moreover, resistance to FGFR2-targeted therapies is a challenge. More sophisticated patient selection strategies would help improve FGFR2-targeted therapies and combination therapy is considered the most promising approach for cancer patients with FGFR2 alterations.     

Keratinocyte growth factor receptor: a therapeutic target in solid cancer

Introduction: The treatment effects of advanced solid cancer are unsatisfactory, and novel therapeutic approaches are much needed. Keratinocyte growth factor receptor (KGFR) is a receptor tyrosine kinase that is primarily localized on epithelial cells. KGFR may play important roles in epithelial cell proliferation and differentiation, epithelial wound repair, embryonic development, immunity, tumor formation and development.

Areas covered: This review summarizes the expression, function and mechanism of KGFR in solid cancer, and analyzes its value for the cancer therapy. Furthermore, this study discusses the limitations of KGFR-based therapy, and envisages future developments in the clinical applications of KGFR.

Expert opinion: KGFR may function as an ideal therapeutic target for solid cancer. Continued basic investigation of KGFR-mediated pathways will push insight into the novel strategies of target therapy. More in vivo studies and clinical trials should be performed to promote the translational bridging of the latest research into clinical application.     

Targeting the HGF/Met signaling pathway in cancer therapy

Introduction: Under normal conditions, hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase (TK), is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand-activated receptor internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis and tumor progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis.

Area covered: The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programs. The authors review Met structure and function, the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development, as well as the latest clinical trial results.

Expert opinion: Clinical trials with HGF/Met pathway antagonists show that as a class these agents are well tolerated. Although widespread efficacy was not seen in several completed Phase II studies, promising results have been reported in lung, gastric, prostate and papillary renal cancer patients treated with these agents. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment are optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents, and model systems available concerning HGF/Met oncogenic signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control.     

Novel approaches to the development of tyrosine kinase inhibitors and their role in the fight against cancer

Introduction: Protein tyrosine kinase inhibitors are currently one of the most important classes of cancer drugs and one of the most impressive approaches of targeted cancer therapy. Aberrant activation of tyrosine kinase pathways is among the most dysregulated molecular pathways in human cancers; therefore, a large number of tyrosine kinases may serve as valuable molecular targets. To date, several inhibitors of tyrosine kinases have been approved and there are hundreds more compounds that are in various stages of development. Because of the deregulation in human malignancies, the ABL1, SRC, the epidermal growth factor receptor and the vascular endothelial growth factor receptor kinases are among the protein kinases that are considered as prime molecular targets for selective inhibition.

Areas covered: This review focuses on most important small-molecule inhibitors that serve as a model for future development. They also provide a broad overview of some of the new approaches and challenges in the field.

Expert opinion: With the exception of a few malignancies seemingly driven by a limited number of genetic lesions, current targeted therapeutic approaches have shown only limited efficacy in advanced cancers. Consequently, more sophisticated strategies, such as identification of pathogenic ‘driver' mutations and optimization of personalized therapies are needed.     

Update on lymphocyte specific kinase inhibitors: a patent survey

Importance of the field: Lck (p56^lck or lymphocyte specific kinase) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T cell receptor (TCR)-mediated signaling, leading to normal T-cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection.

Areas covered in this review: This review covers the patents, patent applications and associated publications for small molecule kinase inhibitors of Lck since 2005 and attempts to place them in context from a structural point of view.

What the reader will gain: Readers will gain an overview of the structural classes and binding modes of Lck inhibitors, the major players in this area and an insight into the current state of the field.

Take home message: The search for a potent and orally active inhibitor of Lck has been an intense area of research for a number of years. Despite tremendous efforts, the identification of a highly selective and potent Lck inhibitor suitable for use as an immunosuppressive agent remains elusive.     

Src kinase inhibitors: an emerging therapeutic treatment option for prostate cancer

Importance of the field: Once prostate cancer becomes castration-resistant, bone metastases are a significant problem and treatment options are limited. As a result, there is a need for more effective therapies that have antitumor and anti-bone metastatic effects. Because Src and Src-family kinases (SFKs) are involved in multiple signaling pathways central to prostate cancer development, progression, and metastasis, in addition to normal and pathologic osteoclast activities, Src inhibition represents a valid therapeutic strategy for investigation.

Areas covered in this review: Here, current treatment options for advanced prostate cancer, the preclinical rationale behind using Src inhibitors, emerging data from clinical trials of Src inhibitors in prostate cancer, and future therapeutic directions are described. Data published in peer-reviewed journals within the last 20 years or presented at recent European or American Society of Clinical Oncology conferences have been reviewed.

What the reader will gain: Readers will gain an insight into the development of therapeutic Src inhibitors, including dasatinib and saracatinib; an understanding of their effects on prostate cancer cells and the bone microenvironment; and emerging clinical data.

Take home message: Src is implicated in prostate cancer progression and metastasis, therefore treatment with Src inhibitors warrants further investigation.     

The potential role of insulin-like growth factor receptor inhibitors in the treatment of advanced non-small cell lung cancer

Importance of the field: Lung cancer is the leading cause of cancer-related mortality worldwide. NSCLC accounts for > 80% of all lung cancers. The treatment of advanced fit NSCLC patients seems to have reached a plateau. Considerable efforts have been initiated to identify new biological agents.

Areas covered in this review: Diagnosis of NSCLC histotype is becoming extremely important to address treatment. While non-squamous histology could start to benefit from the administration of several new drugs only recently, non-adenocarcinoma subtype seems to benefit from the administration of figitumumab (CP-751,871) a fully human anti-IGF 1 receptor (IGF-1R) mAb. In this paper, we reviewed the IGF-1R pathway and its inhibitors.

What the reader will gain: Approaches targeting IGF-1R include small-molecule IGF-1R tyrosine kinase inhibitors (TKIs), which are in preclinical and early clinical phases of development, and the mAbs, among which figitumumab is being investigated in Phase III trials of advanced NSCLC.

Take home message: Figitumumab reported interesting results in the treatment of advanced non-adenocarcinoma NSCLC patients. Overall, in order to administer the optimal treatment to patients, a more definite histological diagnosis is mandatory.     

Hsp90 as a therapeutic target in patients with oesophageal carcinoma

Importance of the field: Oesophageal carcinoma has a poor prognosis with a 5-year overall survival rate of only 10 – 20%. The disease is often diagnosed at a late stage, when dissemination may already have occurred, contributing to the poor prognosis. However, recent developments in targeted therapy now offer new possibilities in the treatment arsenal. Heat shock protein 90 (Hsp90) has been demonstrated to protect oncogenic variants of signalling molecules from degradation, thus promoting cell growth and survival. Hsp90 has been found to be abundantly expressed in oesophageal cancer and may serve as a therapeutic target in the treatment of this disease.

Areas covered in this review: We have summarised available data concerning the role of Hsp90 in oesophageal carcinoma as well as available information on other tumour types.

What the reader will gain: To be able to elaborate on the molecular mechanisms of action of Hsp90 and discuss state-of-the-art of clinical trials involving Hsp90 inhibitors in malignancies, with a special emphasis on oesophageal cancer.

Take home message: Preclinical studies on Hsp90 inhibition in oesophageal cancer are promising and it is anticipated that in the near future clinical trials with Hsp90 inhibitors will be initiated also for oesophageal cancer, using the experience from other trials.     

The expanding role of nilotinib in chronic myeloid leukemia

Importance of the field: Several therapeutic options, including tyrosine kinase inhibitors, exist for the treatment of patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Despite impressive results, there is room for improvement for those patients who are either resistant or intolerant to imatinib.

Areas covered in this review: An overview is given on the clinical results with nilotinib, a rationally designed second-generation tyrosine kinase inhibitor, as first- and second-line therapy in patients with Ph-positive CML. Important factors in predicting resistance to nilotinib and guiding therapeutic decisions are addressed.

What the reader will gain: Knowledge on the clinical efficacy and safety of nilotinib after imatinib failure and as first-line treatment. Point mutations in the kinase domain (KD) of BCR-ABL1 are important determinants of clinical sensitivity to currently available tyrosine kinase inhibitors, including nilotinib. Information on specific BCR-ABL1 KD mutations and safety profiles assist in therapeutic decision making.

Take home message: Nilotinib is a highly effective and well-tolerated therapeutic option in patients with Ph-positive CML after imatinib failure. Early evidence demonstrating increased efficacy has allowed expanding nilotinib to previously untreated patients in chronic phase. Insights into mechanisms of resistance to tyrosine kinase inhibitors and predictive factors for response will allow for a more individualized use of these agents.     

Itk inhibitors: a patent review

Importance of field: IL-2 inducible T-cell kinase (Itk) is a non-receptor tyrosine kinase of the Tec family. It plays an important role in T cell signaling and the production of various pro-inflammatory cytokines such as IL-2, IL-4, IL-5, IL-10 and IL-13. Inhibition of Itk has been a target for the treatment of diseases related to inflammation disorders such as psoriasis and allergic asthma. Rich resources on the structural information for Itk made discovery of novel selective Itk inhibitors blossom in the past decade.

Areas covered in this review: In this report, distinct structural classes of specific Itk inhibitors are summarized and their in vitro/in vivo properties are discussed.

What the reader will gain: A summary of 21 patents including 16 different chemical structure classes of Itk inhibitors. The in vivo efficacies of some of the inhibitors in animal models are also discussed.

Take home message: Although some of the inhibitors show efficacy in different animal models, which implies potential for therapeutic use in human, there is not yet a chemical entity reported in clinical trials. The prospects for Itk inhibitors will rely on the quality of the compound and the validity of the target in patients within the selected therapeutic area.     

Cell cycle inhibitors for the treatment of NSCLC

Introduction: Lung cancer remains to be the leading cause of cancer-related death worldwide. Treatment of lung cancer still poses a significant challenge. Cell cycle is a tightly integrated process and is frequently aberrant in lung cancer. Cell cycle inhibitors have emerged as novel therapeutics, in anticipation of overcoming the unrestricted cell division and growth in lung cancer.

Areas covered: In this article, we first address the potential roles of cell cycle proteins and cell cycle deregulation in the development of lung cancer. The review then provides an overview for several major categories of cell cycle inhibitors with particular attention to their tolerability and disease control in early phases of lung cancer trials.

Expert opinion: Targeted agents against different components of cell cycle regulation, such as cyclin-dependent kinase, polo-like kinase, checkpoint kinase and aurora kinase, are currently in clinical development for lung cancer management. Their clinical benefits remain to be defined. When evaluated as single agents in lung cancer, cell cycle inhibitors are often associated with limited clinical activity and tolerable toxicities. The key challenges in the drug development are to understand resistance mechanisms and to identify predictive biomarkers that can potentially guide patient selection and optimize the utility of these targeted inhibitors.     

The preclinical profile of crizotinib for the treatment of non-small-cell lung cancer and other neoplastic disorders

Introduction: The critical role of the activity of the nucleophosmin- anaplastic lymphoma kinase (NPM-ALK) fusion protein in anaplastic large-cell lymphoma prompted drug discovery programs directed against ALK. Drug discovery efforts increased after finding that about 4% of non-small-cell lung cancers (NSCLCs) possess an EML4-ALK fusion protein.

Areas covered: The author provides a review of the development of crizotinib, an orally effective c-Met and ALK protein kinase inhibitor. The article highlights its beginning with the X-ray crystallographic structure of a lead compound (PHA-0665752) bound to the active site of the kinase domain of c-Met.

Expert opinion: Studies of patients with EML4-ALK–positive NSCLC showed that crizotinib was clinically effective and led to its approval in August 2011. The use of lipophilic efficiency played a crucial role in the development of crizotinib from a lead c-Met inhibitor. The use of X-ray crystal structures from lead compounds, bound to their targets, is increasing in the drug discovery process owing to its effectiveness. That the drug also inhibits ALK and ALK-fusion proteins was serendipitous, however. The discovery of the EML4-ALK fusion protein in some NSCLC patients has led to the testing and rapid approval of the compound.     

Platelet-derived growth factor receptor tyrosine kinase inhibitors: a review of the recent patent literature

Importance of the field: Platelet-derived growth factor receptor (PDGFR) is a compelling target for developing therapeutic agents to treat diseases associated with overactivated platelet-derived growth factor (PDGF) signaling and has proved to be particularly encouraging for cancer treatment. The efforts in this area have been greatly enhanced by the approval of tyrosine kinase inhibitors with PDGFR inhibitory activity such as imatinib, sunitinib and sorafenib.

Areas covered in this review: This review surveys the small molecule PDGFR inhibitors reported in patent literature over the past 5 years (2005 – 2009).

What the reader will gain: The reader will gain an overview of the chemical scaffolds and the activity/selectivity of the newly discovered PDGFR inhibitors.

Take home message: Targeting PDGFR kinase with small molecule inhibitors has remained a very active area. Many new and novel PDGFR inhibitors with different selectivity profiles are being discovered and evaluated. In cancer therapy, the identification of novel and potent PDGFR inhibitors with preferred kinase inhibitory profiles that deliver superior antitumor efficacy, yet have manageable side effects and toxicities, will continue to be the key for success. Additionally, interest in targeting PDGF signaling for intervention of various vascular diseases and fibrotic conditions is expected to continue to grow.