Tyrosine kinase inhibitors under investigation for the treatment of type II diabetes

Introduction: Type 2 diabetes is characterized by hyperglycemia that is the result of β-cell failure in the setting of peripheral insulin resistance. It is estimated that greater than 300 million individuals worldwide have diabetes. Tyrosine kinase inhibitors (TKIs), which are used to treat a variety of cancers, appear to have antihyperglycemic effects.

Areas Covered: This review summarizes studies that have investigated the use of TKIs in animal models of diabetes. Additionally, the authors review case series describing the effects of TKIs on glucose levels in adults taking these drugs for FDA approved indications.

Expert opinion: Given the scope and size of the worldwide diabetes epidemic, reports of amelioration or possible cure of the disease warrant special attention. TKIs appear to lower glucose levels in some, but not all individuals. Multi-center prospective studies are needed in which patient with diabetes treated with TKI undergo phenotyping to identify responders versus non responders to allow for precision medicine.     

Something old,something new and something very old: drugs for treating type 2 diabetes

Diabetes mellitus belongs to the most rapidly increasing diseases worldwide. Approximately 90–95% of these patients suffer from type 2 diabetes mellitus, which is characterized by peripheral insulin resistance and the progressive loss of beta-cell function and mass. Considering the complications of this chronic disease, a reliable anti-diabetic treatment is indispensable. An ideal oral anti-diabetic drug should not only correct glucose homeostasis but also preserve or even augment beta-cell function and mass, ameliorate the subclinical inflammation present under insulin-resistant conditions and prevent the macro- and microvascular consequences of diabetes in order to reduce the mortality. Despite the many anti-diabetic drugs already in use, there is an ongoing research for additional drugs, guided by different concepts of the pathogenesis of type 2 diabetes. This review will briefly summarize current oral anti-diabetic drugs. In addition, emerging strategies for the treatment of diabetes will be described, among them the inhibition of glucagon action and anti-inflammatory drugs. Their suitability as ‘ideal anti-diabetic drugs’ will be discussed.     

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.     

Challenges and opportunities with glycogen synthase kinase-3 inhibitors for insulin resistance and Type 2 diabetes treatment

The role of the serine/threonine protein kinase, glycogen synthase kinase-3 (GSK-3), in attenuating the insulin signalling pathway has led to the concept that inhibition of GSK-3 may have therapeutic benefits in the treatment of insulin resistance and Type 2 diabetes. Indeed, various selective GSK-3 inhibitors have been developed recently and have proven to promote insulin-like effects and to act as insulin sensitisers in both in vitro and in vivo systems. GSK-3 inhibition may thus present a new, effective approach for the treatment of insulin resistance and Type 2 diabetes. This review describes the qualifications of GSK-3 as a novel drug-discovery target for Type 2 diabetes and discusses the strategies and challenges in developing small-molecule inhibitors for this important protein kinase.     

Tyrosine kinase inhibitors to treat liver cancer

Importance of the field: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Although patients with early-stage disease have a good prognosis, there has been no effective therapy available for those with advanced disease. Despite the death risk of patients with advanced HCC being reduced with sorafenib therapy, many patients eventually turn out to be refractory to this therapy. Thus, treatment of HCC remains an urgent health concern.

Areas covered in this review: Recent improvement in understanding the pathophysiology of HCC at the molecular level has fostered the development of molecular targeted therapies that specifically block the disrupted pathways.

What the reader will gain: This review summarizes the preclinical and clinical data from 2004 to 2009 on the efficacy and safety of the emerging drug for the treatment of HCC, including small molecule inhibitors (erlotinib, sunitinib, sorafenib, vandetanib, cediranib, brivanib and dovitinib) and the rationale for combination therapies for patients with advanced HCC.

Take home message: Understanding the mechanisms of action, safety and efficacy of these new agents and new methods of combining these drugs may help prolong overall survival of patients with HCC and reduce disease recurrence after surgery or ablative therapies.     

PTP1B inhibitors as potential therapeutics in the treatment of Type 2 diabetes and obesity

Coordinated tyrosine phosphorylation is essential for signalling pathways regulated by insulin and leptin. Type 2 diabetes and obesity are characterised by resistance to hormones insulin and leptin, possibly due to attenuated or diminished signalling from the receptors. Pharmacological agents capable of inhibiting the negative regulator(s) of the signalling pathways are expected to potentiate the action of insulin and leptin and therefore be beneficial for the treatment of Type 2 diabetes and obesity. A large body of data from cellular, biochemical, mouse and human genetic and chemical inhibitor studies have identified protein tyrosine phosphatase 1B (PTP1B) as a major negative regulator of both insulin and leptin signalling. In addition, evidence suggests that insulin and leptin action can be enhanced by the inhibition of PTP1B. Consequently, PTP1B has emerged as an attractive novel target for the treatment of both Type 2 diabetes and obesity. The link between PTP1B and diabetes and obesity has led to an avalanche of research dedicated to finding inhibitors of this phosphatase. With the combined use of structure and medicinal chemistry, several groups have demonstrated that it is feasible to obtain small-molecule PTP1B inhibitors with the requisite potency and selectivity. The challenge for the future will be to transform potent and selective small molecule PTP1B inhibitors into orally available drugs with desirable physicochemical properties and in vivo efficacies.     

Tyrosine kinase inhibitors in the treatment of unresectable or metastatic gastrointestinal stromal tumors

Introduction: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. Proliferation of GIST is driven by activating mutations in the KIT or PDGFRA genes that found in most sporadic GISTs. Surgery is the main remedial measure for primary GIST, and imatinib is the principal therapeutic of choice for unresectable or metastatic GIST. Imatinib revolutionized treatment for unresectable or metastatic GISTs; however, resistance to imatinib has inevitably developed for most GIST patients.

Areas covered: PubMed was searched to find biological studies of GIST and clinical trials of molecularly targeted agents on unresectable or metastatic GISTs, and the key papers found have been reviewed. In this paper, the standard therapy which includes imatinib, sunitinib and regorafenib for unresectable or metastatic GIST has been reviewed and molecular mechanisms of resistance for tyrosine kinase inhibitors (TKIs) have been postulated and discussed. Treatment measures for resistant GIST and therapeutic choices after the standard therapy have also been described.

Expert opinion: The standard therapy for unresectable or metastatic GISTs is first-line imatinib, second-line sunitinib and third-line regorafenib. After standard therapy, best supportive care or clinical trials is recommended in the guidelines. However, patients may benefit from continuation of TKIs beyond disease progression and from rechallenge of TKIs used previously.     

蛋白酪氨酸激酶抑制剂的研究进展

目的综述蛋白酪氨酸激酶(protein tyrosine kinase,PTK)抑制剂类抗肿瘤药物的研究进展。方法根据已报道的PTK抑制剂的相关文献,将其分为国外已经上市、国外处于临床研究和我国自主研发的PTK抑制剂进行具体介绍。结果 PTK在细胞内的信号转导中起着重要的作用,与肿瘤细胞的生长、增殖、分化和凋亡密切相关,目前已经有多种结构的PTK抑制剂类抗肿瘤药物上市或进入临床研究。结论随着PTK的作用机制及构效关系研究的不断深入,该类药物终将成为治疗肿瘤的有效药物。     

AMPK作为治疗2型糖尿病新靶点的研究进展

2型糖尿病以葡萄糖和脂类的异常代谢为特征,部分归因于周缘组织的胰岛素抵抗。腺苷酸活化蛋白激酶(AMPK)是一种异源三聚体蛋白,由α、β和γ3个亚单位组成。AMPK在调节肌体能量代谢的平衡方面起总开关作用。在肌肉和肝脏中,AMPK的活化增强了葡萄糖的摄取、脂肪酸氧化作用和胰岛素敏感性,并且减少了葡萄糖、胆固醇和甘油三酯的产生。有研究表明,治疗2型糖尿病的一线药物二甲双胍和罗格列酮对机体代谢的影响部分通过AMPK途径。因此,AMPK及其信号通路有望成为治疗肥胖和2型糖尿病的新药理学靶点。     

Tyrosine kinase inhibitors in acute and chronic leukemias

Introduction: Since the initial approval of imatinib much has been learned about its resistance mechanisms, and efforts have continued to improve upon BCR-ABL tyrosine kinase inhibitor therapy. Targeted therapy with TKIs has continued to be an area of active research and development in the care of acute and chronic leukemia patients.

Areas covered: This article reviews current approved and investigational TKI treatments for chronic myelogenous leukemia (CML), Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph + ALL) and acute myelogenous leukemia (AML).

Expert opinion: There are now more potent BCR-ABL TKIs approved, which allow for additional options when determining front-line and second-line CML and Ph + ALL treatments. The T315I mutation is an ever-present challenge. Ponatinib, a pan BCR-ABL TKI, while still under investigation, is very hopeful with its ability to overcome T315I mutations in resistant CML and Ph + ALL patients. Because nilotinib and dasatinib have not been directly compared, at present we recommend selecting one or the other based on the side-effect profile, drug interactions, patient comorbidities, and mutational status. FLT-3 inhibition is of particular interest in AML patients with FLT-3 internal tandem duplication mutations; this type of targeted therapy continues to be studied.     

The JNK pathway as a therapeutic target for diabetes

The hallmark of Type 2 diabetes is insulin resistance and pancreatic β-cell dysfunction. Under diabetic conditions, the c-jun N-terminal kinase (JNK) pathway is activated in various tissues, which is involved in both insulin resistance and β-cell dysfunction. Activation of the JNK pathway interferes with insulin action and reduces insulin biosynthesis, and suppression of the JNK pathway in diabetic mice improves insulin resistance and β-cell function, leading to amelioration of glucose tolerance. Taken together, the JNK pathway is likely to play a central role in the progression of insulin resistance and β-cell dysfunc-tion and, thus, could be a potential therapeutic target for diabe-tes.     

Emerging tyrosine kinase inhibitors for the treatment of metastatic colorectal cancer

Introduction: Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Over the last decade, the addition of antibodies that block the epidermal growth factor receptor (EGFR) or angiogenesis to the classic chemotherapy backbone has improved overall survival in metastatic colorectal cancer (mCRC). However, the role of the other major targeted therapy, the tyrosine kinase inhibitors (TKIs), is not yet fully clarified.

Areas covered: This review discusses key published and ongoing studies with TKIs in mCRC, the mechanisms of resistance to standard treatments that are potentially targetable with these small molecules, along with the role of biomarkers in therapeutic decision-making process.

Expert opinion: The current effectiveness of TKIs is limited by two principal reasons, firstly the use of combination chemotherapy necessitates lower dose-density to manage the toxicity profile and secondly, development of these drugs has mainly been performed in molecularly unselected populations. mCRC is a heterogeneous and dynamic disease, and clinical trials with TKIs must be designed on the basis of specific molecular alterations targeted by these drugs. Success with this approach relies on identifying mutations at the time of progression, raising the importance of minimally-invasive monitoring tools. Liquid biopsies are a promising option, although this technique remains to be validated. Overall, this approach contributes to the move towards personalized and precision therapeutic strategies.     

Emerging tyrosine kinase inhibitors for the treatment of hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) is the fifth most diagnosed cancer in the world and the third leading cause of death. Unfortunately, when diagnosed two thirds of patients have an advanced disease for which only palliative treatment can be proposed and most likely systemic therapy.

Areas covered: As of today only one systemic therapy is validated in the treatment of advanced HCC, a tyrosine kinase inhibitor (TKI): Sorafenib. Treatment options are therefore lacking. With the advent of Sorafenib other TKIs have been studied with some disappointing results. Many explanations can be found to the failure of these tested TKIs such as the underlying cirrhosis leading to rapidly serious adverse events, or trial design imperfections.

Expert opinion: Taking into account these failures, new trials with more appropriate designs have led to recent success with multi-target TKIs (Regorafenib and Lenvatinib). This multi-target approach allows to overcome the molecular heterogeneity of advanced HCC which is associated with multiple simultaneously dysregulated signaling pathways. On the contrary, another lead is to study target a specific TKI such as c-MET inhibitors or TGFβR inhibitors in HCC sub-populations with promising results in early phase trials. These results will have to be validated in the ongoing phase III trials.     

Trk kinase inhibitors as new treatments for cancer and pain

Background: Tropomyosin-related kinases (Trks) are a family of receptor tyrosine kinases activated by neurotrophins. Trks play important roles in pain sensation as well as tumour cell growth and survival signaling. Thus, inhibitors of Trk receptor kinases might provide targeted treatments for pain and cancer. Objective: This paper reviews those patent applications since 2002 claiming small-molecule inhibitors of Trk receptor kinases. Methods: Primary literature and patents were searched with SciFinder and Google Scholar. Patents were selected based on their relevance to Trks and were evaluated and representative compounds were listed as examples. Results/conclusion: Several series of Trk inhibitors with excellent in vitro potencies have been reported and a number of compounds have gone into the clinic. It should be noted that few of these inhibitors are Trk selective, demonstrating that targeting Trk kinases for treatment of pain and/or cancer offers a promising but also challenging approach.     

新型4-苯胺基喹唑啉类酪氨酸激酶抑制剂的抗肿瘤活性研究

目的 对合成的新型4-苯胺基喹唑啉类酪氨酸激酶抑制剂TYIG1～TYIG9进行抗肿瘤活性研究,为寻找具有靶向抗肿瘤活性的候选化合物提供依据。方法 采用均相时间分辨荧光（HTRF）法对化合物进行EGFR、VEGFR-2两个靶点的体外活性筛选;采用MTS法对化合物进行肿瘤细胞（A431、A549、H1975、MDA-MB-231）增殖抑制的体外活性评价;采用人肺癌H1975细胞的移植瘤裸鼠模型评价其在动物体内抗肿瘤活性。结果 采用HTRF法从合成的一系列化合物中筛选出化合物TYIG4~TYIG9对EGFR、VEGFR-2激酶的活性较好。MTS法检测得到这6个化合物对4种肿瘤细胞（A431、A549、H1975、MDA-MB-231）均有不同程度的抑制作用,其中TYIG6的增殖抑制作用的选择性更为突出;体内试验结果表明TYIG6能够剂量相关性地抑制肿瘤生长,50、100 mg/kg TYIG6对H1975的相对肿瘤抑制率分别为42.59%、34.92%。结论 TYIG6具有良好的体内外抗肿瘤活性,具有成为新型双靶点酪氨酸激酶抑制剂的潜能,有进一步的研究价值。     

Dawn of Aurora kinase inhibitors as anticancer drugs

With the current standard chemotherapy regimens only ～ 25% of acute myelogenous leukaemia (AML) patients survive > 5 years. Aurora kinases are overexpressed in many human cancers. VX-680 inhibited Aurora-A, -B, -C and the FMS-like tyrosine kinase-3 with apparent inhibitory constants of 0.6, 18, 4.6 and 30 nM, respectively. In primary leukaemia cells from patients with AML, which were refractory to standard therapies, VX-680 inhibited colony formation. In nude mice, VX-680 markedly reduced human AML tumours. The development of VX-680 for use in AML should continue.     

Emerging drugs for the treatment of gastrointestinal stromal tumour

Introduction: Tyrosine kinase inhibitors (TKIs) have transformed the treatment landscape for patients with gastrointestinal stromal tumors (GIST). Unfortunately, resistance to the currently approved TKIs poses a huge challenge, and patients are in need of additional therapeutic options. Fortunately, many novel therapeutic approaches are being tested in treatment of GIST to overcome resistance to the approved TKIs

Areas covered: We performed an extensive literature (PUBMED) search to identify emerging drugs being tested in treatment of GIST in early phase clinical trials. We discuss recent ongoing research and emerging novel inhibitors of KIT and PDGFRA receptors, inhibitors in downstream signaling pathways (mTOR and PIK3 inhibitors), inhibitors of other potential targets including ETV1/MEK, MET, FGFR, IGF1R, histone deacetylase inhibitors, heat shock protein 90 inhibitors, cyclin-dependent kinase inhibitors and immune checkpoint inhibitors in treatment of GIST

Expert opinion: Multiple agents are under evaluation; those that benefit GIST patients with imatinib resistant mutations, or those with benefit in patients refractory to approved agents are most likely to be developed in this disease. The role of immunotherapy for GIST is still investigational.     

罗格列酮-二甲双胍治疗2型糖尿病疗效评价

胰岛素抵抗及胰岛β细胞功能进行性衰竭是2型糖尿病重要的发病机制.目前应用最广泛的改善胰岛素敏感性的两种药物即马来酸罗格列酮和盐酸二甲双胍,其复合片剂现已成功上市.本品具有良好的血糖控制、减轻胰岛素抵抗和保护胰岛13细胞功能等作用,可改善脂肪代谢和降低心血管事件危险因子及相关标志物水平等.本文简要综述罗格列酮.二甲双胍复方制剂的疗效及安全性.     

Type III or allosteric kinase inhibitors for the treatment of non-small cell lung cancer

Introduction: In recent times, there has been much interest in the development of pharmacological kinase inhibitors that treat NSCLC. Furthermore, treatment options have been guided by the development of a wide panel of synthetic small molecule kinase inhibitors. Most of the molecules developed belong to the type I class of inhibitors that target the ATP-binding site in its active conformation. The high sequence similarity in the ATP-binding site among members of the kinase families often results in low selectivity and additional toxicities. Also, second mutations in the ATP-binding site, such as threonine to methionine at position 790, have been described as a mechanism of resistance to ATP-competitive kinase inhibitors. For these reasons, alternative drug development approaches targeting sites other than the ATP cleft are being pursued. The class III or allosteric inhibitors, which bind outside the ATP-binding site, have been shown to negatively modulate kinase activity.

Areas covered: In this review, the authors discuss the most well-characterised allosteric inhibitors that have reached clinical development in NSCLC.

Expert opinion: Great progress has made in developing inhibitors with entirely new modes of action. That being said, it is important to highlight that despite their apparent simplicity, biochemical assays will remain at the core of drug discovery activities to better explore these new opportunities.