Current Medicinal Chemistry (v.23, #15)

Meet Our Editorial Board Member: by Jens Pietzsch (1495-1495).

Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells by Cristina Corno, Laura Gatti, Cinzia Lanzi, Nadia Zaffaroni, Diego Colombo, Paola Perego (1496-1512).
Aberrant expression and activation of receptor tyrosine kinases (RTK) is a frequent feature of tumor cells that may underlie tumor aggressiveness. Among RTK, Axl, a member of the Tyro3-Axl-Mer family, represents a potential therapeutic target in different tumor types given its over-expression which leads to activation of oncogenic signaling promoting cell proliferation and survival, as well as migration and invasion. Axl can promote aggressiveness of various cell types through PI3K/Akt and/or MAPK/ERK, and its expression can be transcriptionally regulated by multiple factors. Deregulated Axl expression and activation have been shown to be implicated in reduced sensitivity of tumor cells to target-specific and conventional antitumor agents, but the precise mechanism underlying these phenomena are still poorly understood. Several small molecules acting as Axl inhibitors have been reported, and some of them are undergoing clinical investigation. In this review, we describe Axl biological functions, its expression in cancer and in drug-resistant tumor cells and the development of inhibitors tailored to this receptor tyrosine kinase.

New Insight into 2-Methoxyestradiol- a Possible Physiological Link between Neurodegeneration and Cancer Cell Death by Magdalena Gorska, Alicja Kuban-Jankowska, Jaroslaw Slawek, Michal Wozniak (1513-1527).
The pathways leading to development of neurodegenerative disease and cancer cell death may overlap. Interestingly, the main neurodegeneration-causing factors have been suggested to play a pivotal role in the regulation of tumor growth. Another common component in neurodegenerations and cancer is nitro-oxidative stress. Depending on the environmental conditions, the nitro-oxidative stress may lead to cancerogenesis or cancer cell death. On the other side, it may also result in a variety of neurodegenerative diseases.
Based on the literature data, we suggest that 2-methoxyestradiol may be considered as a physiological link between development of neurodegenerations and cancer cell death. 2-methoxyestradiol is a physiological compound, a metabolite of 17β-estradiol. Interestingly, 2-methoxyestradiol, branded as Panzem, is also considered as a potent anticancer agent, currently investigated in several clinical trials. The review aims on making closer the facts concerning anticancer and plausible neurotoxic activities of 2-methoxyestradiol, which may suggest adverse neurological long-term effects of the drug in cancer patients.

Diaryl Urea: A Privileged Structure in Anticancer Agents by Laura Garuti, Marinella Roberti, Giovanni Bottegoni, Mariarosaria Ferraro (1528-1548).
The diaryl urea is an important fragment/pharmacophore in constructing anticancer molecules due to its near-perfect binding with certain acceptors. The urea NH moiety is a favorable hydrogen bond donor, while the urea oxygen atom is regarded as an excellent acceptor. Many novel compounds have been synthesized and evaluated for their antitumor activity with the successful development of sorafenib. Moreover, this structure is used to link alkylating pharmacophores with high affinity DNA binders. In addition, the diaryl urea is present in several kinase inhibitors, such as RAF, KDR and Aurora kinases. Above all, this moiety is used in the type II inhibitors: it usually forms one or two hydrogen bonds with a conserved glutamic acid and one with the backbone amide of the aspartic acid in the DFG motif. In addition, some diaryl urea derivatives act as Hedgehog (Hh) ligands, binding and inhibiting proteins involved in the homonymous Hh signaling pathway. In this review we provide some of the methodologies adopted for the synthesis of diaryl ureas and a description of the most representative antitumor agents bearing the diaryl urea moiety, focusing on their mechanisms bound to the receptors and structure-activity relationships (SAR). An increased knowledge of these derivatives could prompt the search to find new and more potent compounds.

Abscisic Acid: A Phytohormone and Mammalian Cytokine as Novel Pharmacon with Potential for Future Development into Clinical Applications by Priya Sakthivel, Niharika Sharma, Philipp Klahn, Marcus Gereke, Dunja Bruder (1549-1570).
The isoprenoid stress-associated phytohormone abscisic acid (ABA) has recently been recognized to possess multifaceted biological functions in mammals and to exert potent curative effects in a number of clinically relevant human diseases. Studies with human specimens have unequivocally shown that ABA retains its stress-related functional attributes, previously identified in plants, which contribute to enhanced inflammatory defense mechanisms in mammals. Besides, studies performed in animal models revealed prominent anti-inflammatory properties of ABA as indicated by a marked reduction of immune cell infiltrates at the sites of inflammation. Thus, ABA treatment ultimately leads to the profound improvement of both non-communicable and communicable diseases which are associated with an overall alleviated course of inflammation. In addition to its action on the mammalian immune system, ABA was also shown to exert diverse physiological functions on non-immune components. One of the most remarkable features of ABA is to stimulate and expand mesenchymal stem cells, which may open a new avenue for its potential use in the field of regenerative medicine. Furthermore, ABA has been reported to play an important role in the maintenance of glycemic control. In this review, we summarize current understanding of the significance of ABA in the mammalian system, its prophylactic and therapeutic effects in various disease settings and the future directions for the development of ABA as novel drug candidate for the improved treatment of inflammatory and infectious human diseases.

Identifying S100B as a Biomarker and a Therapeutic Target For Brain Injury and Multiple Diseases by Zhao Zhong Chong, Benjarat Changyaleket, Haoliang Xu, Randy O. Dull, David E. Schwartz (1571-1596).
The calcium binding protein S100B has attracted great attention as a biomarker for a variety of diseases. S100B is mainly expressed in glial cells and functions through intracellular and extracellular signaling pathways. The biological roles of S100B have been closely associated with its concentrations and its physiological states. The released S100B can bind to the receptor of advanced glycation end products and induce the initiation of multiple cell signaling transductions. The regulation of S100B bioactivities has been suggested through phosphoinositide 3 kinase/Akt, p53, mitogen-activated protein kinases, transcriptional factors including nuclear factor-kappaB, and cyclic adenosine monophosphate. The levels of S100B in the blood may function to predict the progress or the prognosis of many kinds of diseases, such as cerebrovascular diseases, neurodegenerative diseases, motor neuron diseases, traumatic brain injury, schizophrenia, depression, diabetes mellitus, myocardial infarction, cancer, and infectious diseases. Given that the activity of S100B has been implicated in the pathological process of these diseases, S100B should not be simply regarded as a biomarker, it may also function as therapeutic target for these diseases. Further elucidation of the roles of S100B may formulate innovative therapeutic strategies for multiple diseases.