Current strategies in the discovery of small-molecule biomarkers for Alzheimer's disease

With the number of patients suffering from Alzheimer's disease rapidly increasing, there is a major requirement for an accurate biomarker capable of diagnosing the disease early. Much of the research is focused on protein and genetic approaches; however, small molecules may provide viable marker molecules. Examples that support this approach include known abnormalities in lipid metabolism, glucose utilization and oxidative stress, which have been demonstrated in patients suffering from the disease. Therefore, by-products of this irregular metabolism may provide accurate biomarkers. In this review we present the current approaches previously published in the literature used to investigate potential small-molecule and metabolite markers, and report their findings. A wide range of techniques are discussed, including separation approaches (LC, GC and CE), magnetic resonance technologies (NMR and magnetic resonance spectroscopy), and immunoassays.     

Contemporary medicinal chemistry strategies for the discovery and optimization of influenza inhibitors targeting vRNP constituent proteins

Influenza is an acute respiratory infectious disease caused by the influenza virus, affecting people globally and causing significant social and economic losses. Due to the inevitable limitations of vaccines and approved drugs, there is an urgent need to discover new anti-influenza drugs with different mechanisms. The viral ribonucleoprotein complex (vRNP) plays an essential role in the life cycle of influenza viruses, representing an attractive target for drug design. In recent years, the functional area of constituent proteins in vRNP are widely used as targets for drug discovery, especially the PA endonuclease active site, the RNA-binding site of PB1, the cap-binding site of PB2 and the nuclear export signal of NP protein. Encouragingly, the PA inhibitor baloxavir has been marketed in Japan and the United States, and several drug candidates have also entered clinical trials, such as favipiravir. This article reviews the compositions and functions of the influenza virus vRNP and the research progress on vRNP inhibitors, and discusses the representative drug discovery and optimization strategies pursued.     

作用于Bcl-2家族抗凋亡亚族蛋白的小分子抑制剂的研究进展

细胞的凋亡是维持机体平衡的重要因素。细胞凋亡由一系列细胞因子调控。Bcl-2蛋白家族是细胞凋亡的关键性调节因子。Bcl-2家族分为抗凋亡和促凋亡两个亚族，他们的相互作用对细胞凋亡信号传导起调控作用。很多肿瘤细胞高表达Bcl-2抗凋亡亚族成员Bcl-2/Bcl-xL。近年来，随着Bcl-2家族各成员的晶体结构相继阐明，人们开始寻找作用于Bcl-2家族抗凋亡亚族蛋白的小分子抑制剂。本文从药物设计角度对该方面的进展作一综述。     

Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies

ABSTRACT

Introduction: D-amino-acid oxidase (DAAO) degrades D-serine, a co-agonist of the NMDA receptor whose dysfunction is involved in the positive, negative, and cognitive symptoms of schizophrenia. The inhibition of DAAO appears to be a viable strategy to increase D-serine level and to have therapeutic potential in schizophrenia.

Areas covered: This review describes the efforts to develop DAAO inhibitors and to optimize their in vitro and in vivo effects in preclinical settings. The structural evolution of DAAO inhibitors is presented from simple carboxylic acid derivatives via small, planar compounds with carboxylic acid mimetics to extended compounds whose binding is possible owing to DAAO flexibility. Inhibitory potency and pharmacokinetic properties are discussed in the context of compounds’ ability to increase D-serine level and to show efficacy in animal models of schizophrenia.

Expert opinion: The accumulated knowledge on the structural requirements of DAAO inhibitors and on their in vitro and in vivo effects provides appropriate basis to develop inhibitors with optimized potency, selectivity and pharmacokinetic profile including blood-brain penetration. In addition, the validation of DAAO inhibition therapy in alleviating the symptoms of schizophrenia requires further studies on the efficacy of DAAO inhibitors in behavioral assays of animals and on the species differences in D-serine metabolism.     

Bcl-2蛋白小分子抑制剂的研究进展

目的对近年来Bcl-2蛋白小分子抑制剂的研究进展作以综述。方法根据近期对Bcl-2蛋白小分子抑制剂的21篇相关文献进行整理和归纳。结果和结论Bcl-2蛋白是很有开发潜力的靶点,依据此靶点而设计出的Bcl-2蛋白小分子抑制剂,可以消除或减弱癌细胞对凋亡的耐药性,有望成为新一代抗癌药物。     

Contemporary medicinal-chemistry strategies for the discovery of selective butyrylcholinesterase inhibitors

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Novel methods and strategies in the discovery of TACE inhibitors

Introduction: Tumor necrosis factor-α (TNF-α) is a key player in inflammation and joint damage in rheumatoid arthritis (RA). One treatment approach to exclude TNF-α from the biological system is by inhibiting tumor necrosis factor-alpha converting enzyme (TACE), the enzyme responsible for the production of its active form. To date, a number of TACE inhibitors have been reported in the literature from various strategies and methods.

Areas covered: The following article presents the design and development strategies for the discovery of novel TACE inhibitors which could be of therapeutic utility for the alleviation of inflammatory conditions. The review is based on literature of the subject from 2005 onward.

Expert opinion: Discovery of a selective TACE inhibitor has remained a major goal for many academic and pharmaceutical industrial research laboratories for quite some time. Identification of selective TACE inhibitors has proved elusive until recently due to structural similarities between TACE and MMPs. The differences in the shape and size of the S1′ pocket of TACE and MMPs could be exploited to design selective TACE inhibitors devoid of any MMP inhibitory activity in the near future. It would be a Herculean task to develop a specific TACE inhibitor for clinical treatment of RA because binding subsites of TACE and MMPs are quite similar. However, developments taking place currently in the field as well as in the application of molecular modeling techniques at a wider scale could yet provide clinically useful selective TACE inhibitors in the not too distant future.     

Intrinsically disordered proteins and novel strategies for drug discovery

INTRODUCTION: There is a natural abundance of intrinsically disordered proteins or intrinsically disordered protein regions (IDPs or IDPRs), that is, biologically active proteins/regions without stable structure. Their wide functional repertoire; the ability to participate in multiple interactions; the capability to fold at binding in a template-dependent manner and their common involvement in the pathogenesis of numerous human diseases suggest that these proteins should be seriously considered as novel drug targets. AREAS COVERED: This article describes the major classes of ordered proteins traditionally used as drug targets and introduces the molecular mechanisms of drugs targeting ordered proteins. Furthermore, it illustrates basic ways of rational drug design for these proteins, and shows why these approaches cannot be directly used for intrinsic disorder-based drug design. Some of the new approaches utilized for finding drugs targeting IDPs/IDPRs are introduced. EXPERT OPINION: There is a continuing progress in the design of small molecules for IDPs/IDPRs and several small molecules are found that specifically inhibit the disorder-based interaction of IDPs with their numerous partners. It is expected that the initial studies will be extended and novel intrinsic disorder-based drug design approaches will be developed. Furthermore, putative new targets will be identified, and a better understanding of the molecular mechanisms underlying modulation of promiscuous IDP binding will be achieved.     

Intrinsically disordered proteins and novel strategies for drug discovery

Introduction: There is a natural abundance of intrinsically disordered proteins or intrinsically disordered protein regions (IDPs or IDPRs), that is, biologically active proteins/regions without stable structure. Their wide functional repertoire; the ability to participate in multiple interactions; the capability to fold at binding in a template-dependent manner and their common involvement in the pathogenesis of numerous human diseases suggest that these proteins should be seriously considered as novel drug targets.

Areas covered: This article describes the major classes of ordered proteins traditionally used as drug targets and introduces the molecular mechanisms of drugs targeting ordered proteins. Furthermore, it illustrates basic ways of rational drug design for these proteins, and shows why these approaches cannot be directly used for intrinsic disorder-based drug design. Some of the new approaches utilized for finding drugs targeting IDPs/IDPRs are introduced.

Expert opinion: There is a continuing progress in the design of small molecules for IDPs/IDPRs and several small molecules are found that specifically inhibit the disorder-based interaction of IDPs with their numerous partners. It is expected that the initial studies will be extended and novel intrinsic disorder-based drug design approaches will be developed. Furthermore, putative new targets will be identified, and a better understanding of the molecular mechanisms underlying modulation of promiscuous IDP binding will be achieved.     

Structure-based design of flavonoid compounds as a new class of small-molecule inhibitors of the anti-apoptotic Bcl-2 proteins

Structure-based strategy was employed to design flavonoid compounds to mimic the Bim BH3 peptide as a new class of inhibitors of the anti-apoptotic Bcl-2 proteins. The most potent compound, 4 (BI-33), binds to Bcl-2 and Mcl-1 with Ki values of 17 and 18 nM, respectively. Compound 4 inhibits cell growth in the MDA-MB-231 breast cancer cell line with an IC50 value of 110 nM and effectively induces apoptosis.     

HIV-1融合抑制剂研究现状及发展趋势

HIV-1融合抑制剂是继逆转录酶和蛋白酶抑制剂后的新一类抗HIV感染药物, 通过阻断病毒与靶细胞膜的融合从而抑制病毒进入靶细胞, 在感染的初始环节切断HIV-1的传播, 其中多肽类融合抑制剂T-20已于2003年上市。HIV-1融合抑制剂以HIV-1跨膜糖蛋白gp41为作用靶标, 它们是一些天然或合成的多肽以及小分子化合物, 通过与gp41功能区结合从而抑制其促融合功能的发挥。近年来, 随着对膜融合过程分子机制以及gp41功能研究的不断深入, 新的以gp41不同功能区为靶点的融合抑制剂分子不断被发现, 成为倍受关注的研究热点之一。本文着重对近年来HIV-1融合抑制剂的研究现状及发展趋势进行综述。     

Recent advances in the discovery of small-molecule ATP competitive mTOR inhibitors: a patent review

Introduction: The mammalian target of rapamycin (mTOR) is a protein kinase and a key component of the PI3K/Akt/mTOR signaling pathway, and is deregulated in half of all human cancers. Rapamycin and its analogs (rapalogs) are allosteric inhibitors of one functional mTOR complex, mTORC1, and are clinically proven therapeutic agents for the treatment of certain cancers. However, rapalogs mainly partially inhibit mTORC1, while ATP competitive inhibitors suppress both mTORC1 and mTORC2, and therefore may offer advantages in the clinic. Recently, small-molecule inhibitors have entered clinical trials that are mTOR-selective or dual mTOR/PI3K inhibitors.

Areas covered: This review focuses on ATP-competitive mTOR inhibitors that have appeared in the patent literature in 2010. Many inhibitors with new structural motifs have been discovered as well as inhibitors that are related to previously disclosed structures. This review endeavors to put into perspective the diverse structural elements that make up these compounds. Patent applications are covered that include either selective mTOR inhibitors or dual mTOR/PI3K inhibitors.

Expert opinion: The PI3K/mTOR signaling pathway is an exciting target for the development of pharmaceuticals to treat cancer and other diseases, due to the unique combination of a clinically and commercially validated pathway approach (i.e., rapalogs), combined with a biological rationale for further increased efficacy (i.e., ATP-competitive inhibitors). With the number of candidate drugs currently in development or at earlier stages of the drug discovery pipeline, we are bound to see small-molecule inhibitors reach pivotal trials, and hopefully the market, in the near future.     

Recent advances in the discovery of small-molecule ATP competitive mTOR inhibitors: a patent review

INTRODUCTION: The mammalian target of rapamycin (mTOR) is a protein kinase and a key component of the PI3K/Akt/mTOR signaling pathway, and is deregulated in half of all human cancers. Rapamycin and its analogs (rapalogs) are allosteric inhibitors of one functional mTOR complex, mTORC1, and are clinically proven therapeutic agents for the treatment of certain cancers. However, rapalogs mainly partially inhibit mTORC1, while ATP competitive inhibitors suppress both mTORC1 and mTORC2, and therefore may offer advantages in the clinic. Recently, small-molecule inhibitors have entered clinical trials that are mTOR-selective or dual mTOR/PI3K inhibitors. AREAS COVERED: This review focuses on ATP-competitive mTOR inhibitors that have appeared in the patent literature in 2010. Many inhibitors with new structural motifs have been discovered as well as inhibitors that are related to previously disclosed structures. This review endeavors to put into perspective the diverse structural elements that make up these compounds. Patent applications are covered that include either selective mTOR inhibitors or dual mTOR/PI3K inhibitors. EXPERT OPINION: The PI3K/mTOR signaling pathway is an exciting target for the development of pharmaceuticals to treat cancer and other diseases, due to the unique combination of a clinically and commercially validated pathway approach (i.e., rapalogs), combined with a biological rationale for further increased efficacy (i.e., ATP-competitive inhibitors). With the number of candidate drugs currently in development or at earlier stages of the drug discovery pipeline, we are bound to see small-molecule inhibitors reach pivotal trials, and hopefully the market, in the near future.     

A historical sketch of the discovery and development of HIV-1 integrase inhibitors

The long process of HIV-1 integrase inhibitor discovery and development can be attributed to both the complexity of HIV-1 integration and poor 'integration' of these researches into mainstream investigations on antiretroviral therapy in the mid-1990s. Of note, some fungal extracts investigated during this period contain the beta-hydroxyketo group, later recognised to be a key structural requirement for keto-enol acids (also referred to as diketo acids) and other integrase inhibitors. This review reconstructs (in the general context of the history of AIDS research) the principal steps that led to the integrase inhibitors currently in clinical trials, and discusses possible future directions.     

A historical sketch of the discovery and development of HIV-1 integrase inhibitors

The long process of HIV-1 integrase inhibitor discovery and development can be attributed to both the complexity of HIV-1 integration and poor ‘integration’ of these researches into mainstream investigations on antiretroviral therapy in the mid-1990s. Of note, some fungal extracts investigated during this period contain the β-hydroxyketo group, later recognised to be a key structural requirement for keto-enol acids (also referred to as diketo acids) and other integrase inhibitors. This review reconstructs (in the general context of the history of AIDS research) the principal steps that led to the integrase inhibitors currently in clinical trials, and discusses possible future directions.     

Computer-aided drug design strategies used in the discovery of fructose 1, 6-bisphosphatase inhibitors

Computational assessment of the binding affinity of enzyme inhibitors prior to synthesis is an important component of computer-aided drug design (CADD) paradigms. The free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities between two inhibitors. However, due to its complexity and computation-intensive nature, practical applications are restricted to analysis of structurally-related inhibitors. Accordingly, there is a need for methods that enable rapid assessment of a large number of structurally-unrelated molecules in a suitably accurate manner. In this review, the FEP method is compared with molecular mechanics (MM) methods to assess the advantages of each in the estimation of relative binding affinities of inhibitors to an enzyme. Qualitative predictions of relative binding free energies of fructose 1, 6-bisphosphatase inhibitors using MM methods are discussed and compared with the corresponding FEP results. The results indicate that the MM based methods and the FEP method are useful in the qualitative and quantitative assessment of relative binding affinities of enzyme inhibitors, respectively, prior to synthesis.     

Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers

Tropomyosin receptor kinase A, B and C (TRKA, TRKB and TRKC), which are well-known members of the cell surface receptor tyrosine kinase (RTK) family, are encoded by the neurotrophic receptor tyrosine kinase 1, 2 and 3 (NTRK1, NTRK2 and NTRK3) genes, respectively. TRKs can regulate cell proliferation, differentiation and even apoptosis through the RAS/MAPKs, PI3K/AKT and PLCγ pathways. Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors, and TRKs have become promising antitumor targets. Therefore, achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications. This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins, the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity, and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.KEY WORDS: Tropomyosin receptor kinase, Neurotrophic receptor tyrosine kinase fusions, Small-molecule inhibitor, NTRK fusion cancer     

靶向ROS1酪氨酸激酶小分子抑制剂的研究进展

目的综述c-ros原癌基因1(c-ros oncogene 1,ROS1)酪氨酸激酶的结构和功能及其抑制剂的研究进展。方法查阅近年来国内外相关文献47篇,对其进行归纳总结和分析。结果 ROS1作为一个关键的跨膜受体蛋白酪氨酸激酶,控制细胞凋亡、生存、分化及增殖等多个细胞进程,对多种恶性肿瘤的治疗有重要作用,因此,开发ROS1抑制剂具有重要的价值。2015年4月,克唑替尼(crizotinib)被美国FDA授予突破性药物资格,用于ROS1阳性非小细胞肺癌的潜在治疗;随后2-氨基嘧啶类、4-芳氨基喹啉类等化合物相继被报道具有较强的ROS1激酶抑制活性,此外,一些选择性ROS1抑制剂(如化合物12)也被开发出来。结论尽管目前对ROS1选择性抑制剂研究较少,但ROS1抑制剂仍具有良好的开发前景。     

Pin1及其小分子抑制剂的研究进展

Pin1(protein interaction with NIMA1)是一种肽脯氨酰顺反异构酶,其在致癌信号通路中发挥着整合、翻译和放大等重要作用。越来越多的研究表明Pin1有望成为新的肿瘤诊断和治疗的理想靶标。国内外早期对Pin1抑制剂的研究主要集中在拟肽类化合物,但由于其成药性差而难以应用于临床的先天缺陷导致近年的研究热点转移到Pin1小分子抑制剂的开发。本文综述了Pin1的生物学功能及其小分子抑制剂的最新研究进展。     

New strategies in the discovery of novel non-camptothecin topoisomerase I inhibitors

Topoisomerase I (Top1) represents an important target of active interest in developing novel anticancer agents. Camptothecin derivatives are the only class of clinically approved Top1 inhibitors and show potent efficacy in anticancer therapy. However, there are also several major limitations for them, such as poor chemical stability, drug resistance, long infusions and side effects. To overcome the drawbacks of the camptothecins, the discovery of non-camptothecin Top1 inhibitors has recently emerged as a promising field to find better antitumor agents. Non-camptothecin Top1 inhibitors are expected to possess better chemical stability, different therapeutic activities and antitumor spectrum, improved pharmacokinetics and lower toxicity. This review focuses on various strategies that were used in the discovery of non-camptothecin Top1 inhibitors. In particular, the chemical scaffolds, structure-activity relationships and binding modes of the newly identified non-camptothecin Top1 inhibitors are discussed in detail.