Current Medicinal Chemistry (v.24, #19)

Recent Findings on the Application of Toll-like Receptors Agonists in Cancer Therapy by Martina Mikulandra, Jasminka Pavelic, Tanja Matijevic Glavan (2011-2032).
The immune system’s first line of defense is innate immunity, largely based on a large family of pattern recognition receptors (PRRs) that recognize evolutionary conserved molecular motifs on pathogens called pathogen-associated molecular patterns (PAMPs). The most extensively studied family of PRRs is Toll-like receptors (TLRs), which can trigger various cellular pathways after ligand stimulation. Their role in cancer is still unresolved as there are many different studies showing contradictory results. TLRs have been associated with both tumor progression and immunosuppression as well as with apoptosis and immune system activation. With their ability to induce apoptotic response and activation of innate and adaptive immunity, TLRs are an interesting pharmacological target for the development of anticancer therapy. There are numerous studies including the clinical trials reviewed in this paper, indicating that TLR agonists, especially combined with other more conventional therapies such as chemotherapy and radiotherapy, are promising adjuvants or components of newly developed treatment regimens. Still, the increasing number of studies indicating protumorigenic consequences of TLR activation in various cancer types and recent reports of the existence of endogenous TLR ligands, forewarn that more studies on this topic are required before their inclusion into regular clinical practice.

Discovery of Hedgehog Antagonists for Cancer Therapy by Harleen Khatra, Chandra Bose, Surajit Sinha (2033-2058).
Background: The evolutionarily conserved Hedgehog (Hh) signaling cascade is one of the key mediators of embryonic development of many metazoans. This pathway has been extensively targeted by small molecule inhibitors as its misregulation leads to various malignancies and developmental disorders. Thus, blocking this pathway can be a novel therapeutic avenue for the treatment of Hedgehog-dependent cancers. This review covers the mechanism of hedgehog signaling in vertebrate cells, provides an overview of reported small molecule Hh pathway inhibitors, with the synthetic routes and SAR studies of some of them discussed briefly. <P></P> Methods: A comprehensive survey of literature related to synthetic and naturally occurring Hh signaling antagonists reported till date is presented. <P></P> Results: Given the selectivity of small molecules targeting, this pathway for cancer treatment compared to kinase, tubulin or HDAC inhibitors, several such antagonists have been discovered, of which some are in preclinical development and clinical studies. Most of the reported small molecules primarily antagonize the Smoothened receptor although agents targeting Gli1 transcription factor and Shh ligand have also been discovered. Till date, nine Smo antagonists have been evaluated in clinical trials.GDC- 0449/Vismodegib and NVP-LDE225/Erismodegib, were granted approval by the U.S. Food and Drug Administration (U.S. FDA) for the treatment of basal cell carcinoma. <P></P> Conclusion: The challenge is to identify agents that target the pathway downstream of Smo and develop strategies to overcome acquired drug resistance to the current Smo inhibitors with deeper understanding of the resistance mechanisms.

Pyrrolo[2,3-d]Pyrimidines as Kinase Inhibitors by Francesca Musumeci, Monica Sanna, Giancarlo Grossi, Chiara Brullo, Anna Lucia Fallacara, Silvia Schenone (2059-2085).
The pyrrolo[2,3-d]pyrimidine nucleus is a deaza-isostere of adenine, the nitrogenous base of ATP, and is present in many ATP-competitive inhibitors of different kinases. In the last few years the number of articles and patents that have appeared involving this type of inhibitors has dramatically increased and some compounds have been approved for the treatment of inflammatory or myeloproliferative diseases. Other derivatives are currently being evaluated in clinical trials. This review deals with pyrrolo[2,3- d]pyrimidine derivatives active as kinase inhibitors that have been reported in the literature from 2011 to 2016, with a particular interest on the recently patented compounds. The molecules are classified depending on the inhibited kinase, focusing on their chemical structures.

Mitochondria-targeted Antioxidants as a Prospective Therapeutic Strategy for Multiple Sclerosis by Elena Fetisova, Boris Chernyak, Galina Korshunova, Maria Muntyan, Vladimir Skulachev (2086-2114).
Background: Multiple sclerosis (MS) is one of the most widespread chronic neurological diseases that manifests itself by progressive demyelination in the central nervous system. The study of MS pathogenesis begins with the onset of the relapsing–remitting phase of the disease, which becomes apparent due to microglia activation, neuroinflammation and demyelination/ remyelination in the white matter. The following progressive phase is accompanied by severe neurological symptoms when demyelination and neurodegeneration are spread to both gray and white matter. In this review, we discuss a possible role of mitochondrial reactive oxygen species (mtROS) in MS pathogenesis, mechanisms of mtROS generation and effects of some mitochondria-targeted antioxidants as potential components of MS therapy. <P></P> Results: In the early phase of MS, mtROS stimulate NLRP3 inflammasomes, which is critical for the formation of local inflammatory lesions. Later, mtROS contribute to blood-brain barrier disruption induced by mediators of inflammation, followed by infiltration of leukocytes. ROS generated by leukocytes and activated microglia promote mitochondrial dysfunction and oligodendrocyte cell death. In the progressive phase, neurodegeneration also depends on excessive mtROS generation. Currently, only a few immunomodulatory drugs are approved for treatment of MS. These drugs mainly reduce the number of relapses but do not stop MS progression. Certain dietary and synthetic antioxidants have demonstrated encouraging results in animal models of MS but were ineffective in the completed clinical trials. <P></P> Conclusion: Novel mitochondria-targeted antioxidants could be promising components of combined programs for MS therapy considering that they can be applied at extremely low doses and concurrently demonstrate anti-inflammatory and neuroprotective activities.

Antimicrobial Polymers: Mimicking Amino Acid Functionali ty, Sequence Control and Three-dimensional Structure of Host-defen se Peptides by Matthias Hartlieb, Elizabeth G. L. Williams, Agnès Kuroki, Sébastien Perrier, Katherine E. S. Locock (2115-2140).
Peptides and proteins control and direct all aspects of cellular function and communication. Having been honed by nature for millions of years, they also typically display an unsurpassed specificity for their biological targets. This underlies the continued focus on peptides as promising drug candidates. However, the development of peptides into viable drugs is hampered by their lack of chemical and pharmacokinetic stability and the cost of large scale production. One method to overcome such hindrances is to develop polymer systems that are able to retain the important structural features of these biologically active peptides, while being cheaper and easier to produce and manipulate chemically. <P></P> This review illustrates these principles using examples of polymers designed to mimic antimicrobial host-defence peptides. The host-defence peptides have been identified as some of the most important leads for the next generation of antibiotics as they typically exhibit broad spectrum antimicrobial ability, low toxicity toward human cells and little susceptibility to currently known mechanisms of bacterial resistance. Their movement from the bench to clinic is yet to be realised, however, due to the limitations of these peptides as drugs. The literature provides a number of examples of polymers that have been able to mimic these peptides through all levels of structure, starting from specific amino acid sidechains, through to more global features such as overall charge, molecular weight and threedimensional structure (e.g. α-helical). The resulting optimised polymers are able retain the activity profile of the peptides, but within a synthetic macromolecular construct that may be better suited to the development of a new generation of antimicrobial therapeutics. Such work has not only produced important new leads to combat the growing threat of antibiotic resistance, but may also open up new ways for polymers to mimic other important classes of biologically active peptides.