Multi-Target Drug Discovery – Part II

Editorial Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 28 3081 EDITORIAL Multi-target Drug Discovery – Part II Like other multigenic diseases, cancer also arises from a complicated network of interdependent pathological changes. Traditional cytotoxic drugs have encountered many limitations such as lack of efficacy, severe side effects and resistance, which prompts the interests in developing more efficacious and safer targeted therapies [1]. Despite enormous advancements in medical knowledge, the outcome of cancer treatment is still far from satisfactory. The design idea of anti-cancer drugs undergoes the evolution from "one-compound-one-target", to "cocktail therapy", and recently "multi-target approach" [2]. With the successful development of several drugs, such as sorafenib (approved by the U.S. Food and Drug Administration in 2005), regorafenib (2012), lapatinib (2007), sunitinib (2006), vatalanib (2011), bosutinib (2012), radotinib (2012), and midostaurin (2017), multi-target-directed ligands (MTDLs) in cancer therapy is more established. Several promising candidates are undergoing clinical trials, such as voxtalisib (SAR245409, phase I/II) [3], golvatinib (DCC-2036, phase I/II) [4], and flavopiridol (alvocidib, phase II) [5]. Contributed by our group in this special issue, six categories of anti-cancer arylurea derivatives including monoaryl, diaryl, and aromatic heterocyclic ureas were reviewed. Their structure–activity relationships (SARs) were discussed. The structural evolution and current status of some typical anti-cancer agents used in clinical trials and/or clinical practice were emphasized. Contributed by F.Y. Wang et al. in this special issue, the recent development of organic multi-targeted anti-cancer agents and metal-based complexes was covered. It should be noted that metal complexes, a unique class of dual- or multi-targeted anti-cancer agents, have attracted more and more attention in the recent years [6]. Because most of the MTDLs are organic compounds and metal complexes are relatively scarce, the research of multi-target metal-based anti-cancer agents represents a new field. Up to date, the therapeutic potential of metal complexes is undervalued and the detailed mechanisms remain unclear. In this special issue, the recent progress of multi-target metal-based anti-cancer agents was reviewed by Z.F. Chen et al. These agents include platinum(II), ruthenium(II), rhodium(I), gold(III), copper(II), cobalt(II), zinc(II), nickel(II), and chromium(II) complexes. In the future, besides pursuing high selectivity and efficacy, their mechanism of investigation should also be given priority to. The main hindrance in tumor chemotherapy includes the development of resistance in tumor cells against cytotoxic agents. Due to broad structural resistance to cytostatics, it is termed as Multidrug Resistance (MDR). So far, researchers have been struggling to overcome or circumvent MDR in cancer therapy. However, efforts by using MDR modulators in clinical trials in the past 20 years have not yielded promising results [7, 8]. Inflammation is likewise a complicated biological process which implicates a great number of mediators originating from the over-activation of multiple cascades. These regulatory factors include Cyclooxygenase (COX), 5-Lipoxygenase (5-LOX), Interleukins (IL), Prostaglandins (PGs), Nitric Oxide Synthase (NOS), Nuclear Factor-κB (NF-κB), Intracellular Cell Adhesion Molecule-1 (ICAM-1), and so on [9-11]. Contributed by S.K. Bharti et al. in this special issue, various derivatives based on chalcone modified by hydroxyl, methoxyl, carboxyl, the prenyl group and heterocyclic rings were reviewed. The SARs, multi- targeting properties, and patents of these derivatives were highlighted. This review may be helpful for medicinal chemists to design selective, more potent, and safer chalcone-based anti-inflammatory agents. In Part I, the design strategy of multi-targeted hybrids is widely adopted to obtain anti-Alzheimer's Disease (anti-AD) agents. In fact, this concept has also been utilized in anti-cancer and anti-inflammatory agent design. In most cases, the hybrid molecules are obtained by the combination of two or more biologically active moieties, they have the advantages of reduced undesired side effects, improved affinity, and enhanced efficacy [12]. A number of hybrids have been prepared and evaluated in the last decade, such as benzoselenazole-stilbene [13], coumarin-monastrol [14], podophyllotoxin-norcantharidin [15], and NOSH-aspirin [16]. Specially, hybrids based on natural pharmacophoric groups become more and more popular. Some natural products themselves exhibit superior multiple-targeted properties; therefore, whether natural product used alone [17], simple structural modification [18], or its hybrid by incorporating some moiety may result in the generation of lead compounds, even MTDLs with high performance [19]. An old topic–the association between inflammation and cancer has already been first described in the 19th century by Rudolf Virchow [20]. Inflammation (especially chronic inflammation) is now considered a dominant feature and a hallmark of cancer and linked to various steps including survival, proliferation, angiogenesis, invasion, and metastasis [21, 22]. Several pro- inflammatory gene products associated with malignancy including TNF, interleukin family (IL-1a, IL-1b, IL-6, IL-8, IL-18), Matrix Metalloproteinase-9 (MMP-9), Cytokines, Vascular Endothelial Growth Factor (VEGF), COX-2, and 5-LOX have been identified. The expression of all these genes is mainly regulated by the transcription factor NF-κB, which is constitutively active in most tumors [23]. However, the above is not a detailed description because different inflammation types correspond to different cancers which involve various targets, it is almost impossible to find a universal mechanism that summarizes the cor- relation between all of the inflammation types and cancers. In addition, anti-inflammatory therapy is efficacious towards early neoplastic progression and malignant conversion. For example, Non-Steroidal Anti-Inflammatory Drug (NSAID) aspirin can 1873-4294/17 $58.00+.00 © 2017 Bentham Science Publishers 3082 Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 28 Editorial reduce the incidence of some cancers and effectively prevent metastasis [24]. Treating a cancer patient in the future may involve not only the use of anticancer drugs but also therapeutic agents associated with chronic inflammation in this disease [25]. At the end of the editorial, several issues should be paid much attention to in the design and development of MTDLs: (1) Which ones are critical targets? In the discovery of MTDLs, one of the bottlenecks is to find those critical targets which directly take part in the occurrence and progress of the disease. We will lose our way and make mistakes if they are wrongly selected. In this sense, as described in Part I, accurate pharmacological and mechanistic investigations of the disease (e.g., cancer, AD, and inflammation) are absolutely essential. However, limitations in target validation and other factors greatly lengthened the research and development periods of MTDLs. (2) How to adjust the ratio of different pharmacophores? Unlike “cocktail therapy” in which the ratio of each component is adjustable based upon clinical requirements, each compound of MTDL has a specific chemical structure, which means that the ratio of each pharmacophore in the molecular structure usually cannot be changed. However, different targets correspond to different dosages or concentrations. It is necessary to consider the ratio of different pharmacophores in the earlier and less expensive stage to avoid unnecessary waste. Of course, this will inevitably increase the complexity in the design and optimization of the MTDLs. Up to date, there are only a limited number of reports concerning the ratio design of pharmacophores. (3) Druggability assessment: Although a number of synthesized dual- and multi-targeted compounds (especially anti-AD and anti-cancer agents) have shown favorable efficacy in vitro, most still fail in clinical trials due to suboptimal pharmacokinetics profiles and/or unexpected toxicities. Therefore, the investigation of the n-octanol/water partition coefficients (Ko/w) should be given adequate attention. By using multiple kinds of Computer-Aided Drug Discovery (CADD) software, we can predict Ko/w and toxicity of a promising candidate. In fact, based on the will help developers eliminate those compounds which are not worthy of intensive study as early as possible, thereby avoiding the waste of manpower, materials, and financial resources. (4) Great importance should be attached to resistance-related targets and exact mechanisms of MDR. Currently, pharmacological activities such as anti-AD, anti-inflammatory, or antineoplastic effects are emphasized, even exag- gerated; however, the drug resistance is underestimated. In general, the research and development of novel MTDLs with higher therapeutic indexes, lower side effects, and weaker tendency to induce resistant phenotypes are still a great challenge. As a guest editor, I would like to express my gratitude to those authors who contributed to this special issue and covered the recent developments in various aspects of "Multi-target Drug Discovery". I also express my appreciation to the editors of the journal "Current Topics in Medicinal Chemistry", especially associate editor Professor Ambreen Irshad who has put in a tre-

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