Current Medicinal Chemistry - Volume 27, Issue 32, 2020

Eighty-five percent of patients with lung cancer present with Non-small Cell Lung Cancer (NSCLC). Targeted therapy approaches are promising treatments for lung cancer. However, despite the development of targeted therapies using Tyrosine Kinase Inhibitors (TKI) as well as monoclonal antibodies, the five-year relative survival rate for lung cancer patients is still only 18%, and patients inevitably become resistant to therapy. Mutations in Kirsten Ras Sarcoma viral homolog (KRAS) and epidermal growth factor receptor (EGFR) are the two most common genetic events in lung adenocarcinoma; they account for 25% and 20% of cases, respectively. Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor tyrosine kinase, and ALK rearrangements are responsible for 3-7% of NSCLC, predominantly of the adenocarcinoma subtype, and occur in a mutually exclusive manner with KRAS and EGFR mutations. Among drug-resistant NSCLC patients, nearly half exhibit the T790M mutation in exon 20 of EGFR. This review focuses on some basic aspects of molecules involved in NSCLC, the development of resistance to treatments in NSCLC, and advances in lung cancer therapy in the past ten years. Some recent developments such as PD-1-PD-L1 checkpoint-based immunotherapy for NSCLC are also covered.

Background: Metabolic reprogramming of tumours is a hallmark of cancer. Among the changes in the metabolic network of cancer cells, glutaminolysis is a key reaction altered in neoplasms. Glutaminase proteins control the first step in glutamine metabolism and their expression correlates with malignancy and growth rate of a great variety of cancers. The two types of glutaminase isoenzymes, GLS and GLS2, differ in their expression patterns and functional roles: GLS has oncogenic properties and GLS2 has been described as a tumour suppressor factor. Results: We have focused on glutaminase connections with key oncogenes and tumour suppressor genes. Targeting glutaminase isoenzymes includes different strategies aimed at deactivating the rewiring of cancer metabolism. In addition, we found a long list of metabolic enzymes, transcription factors and signalling pathways dealing with glutaminase. On the other hand, a number of chemicals have been described as isoenzyme-specific inhibitors of GLS and/or GLS2 isoforms. These molecules are being characterized as synergic and therapeutic agents in many types of tumours. Conclusion: This review states the metabolic pathways that are rewired in cancer, the roles of glutaminase isoforms in cancer, as well as the metabolic circuits regulated by glutaminases. We also show the plethora of anticancer drugs that specifically inhibit glutaminase isoenzymes for treating several sets of cancer.

Drug repositioning is an important area of biomedical research. The drug repositioning studies have shifted to computational approaches. Large-scale perturbation databases, such as the Connectivity Map and the Library of Integrated Network-Based Cellular Signatures, contain a number of chemical-induced gene expression profiles and provide great opportunities for computational biology and drug repositioning. One reason is that the profiles provided by the Connectivity Map and the Library of Integrated Network-Based Cellular Signatures databases show an overall view of biological mechanism in drugs, diseases and genes. In this article, we provide a review of the two databases and their recent applications in drug repositioning.

Alzheimer’s Disease (AD) is a chronic neurodegenerative disorder characterized by cognitive impairments such as memory loss, decline in language skills, and disorientation that affects over 46 million people worldwide. Patients with AD also suffer from behavioral and psychological symptoms of dementia that deteriorate their quality of life and lead to premature death. Currently available drugs provide modest symptomatic relief but do not reduce pathological hallmarks (senile plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of dementia. A large body of evidence indicates that impaired signaling pathways of cyclic-3′,5′- Adenosine Monophosphate (cAMP) and cyclic-3′,5′-guanosine Monophosphate (cGMP) may contribute to the development and progression of AD. In addition, Phosphodiesterase (PDE) inhibitors, commonly known as cAMP and/or cGMP modulators, were found to be involved in the phosphorylation of tau; aggregation of amyloid beta; neuroinflammation; and regulation of cognition, mood, and emotion processing. The purpose of this review was to update the most recent reports on the development of novel multifunctional ligands targeting PDE as potential drugs for both symptomatic and disease-modifying therapy of AD. This review collected the chemical structures of representative multifunctional ligands, results of experimental in vitro and in vivo pharmacological studies, and current opinions regarding the potential utility of these compounds for the comprehensive therapy of AD. Finally, the multiparameter predictions of drugability of the representative compounds were calculated and discussed.

Traumatic Brain Injury (TBI) is a major public health problem. It is the leading cause of death and disability, especially among children and young adults. The neurobiology basis underlying TBI pathophysiology remains to be fully revealed. Over the past years, emerging evidence has supported the hypothesis that TBI is an inflammatory based condition, paving the way for the development of potential therapeutic targets. There is no treatment capable to prevent or minimize TBIassociated outcomes. Therefore, the search for effective therapies is a priority goal. In this context, animal models have become valuable tools to study molecular and cellular mechanisms involved in TBI pathogenesis as well as novel treatments. Herein, we discuss therapeutic strategies to treat TBI focused on immunomodulatory and/or anti-inflammatory approaches in the pre-clinical setting.

Parasitic diseases, caused by helminths (ascariasis, hookworm, trichinosis, and schistosomiasis) and protozoa (chagas, leishmaniasis, and amebiasis), are considered a serious public health problem in developing countries. Additionally, there is a limited arsenal of anti-parasitic drugs in the current pipeline and growing drug resistance. Therefore, there is a clear need for the discovery and development of new compounds that can compete and replace these drugs that have been controlling parasitic infections over the last decades. However, this approach is highly resource- intensive, expensive and time-consuming. Accordingly, a drug repositioning strategy of the existing drugs or drug-like molecules with known pharmacokinetics and safety profiles is alternatively being used as a fast approach towards the identification of new treatments. The artemisinins, mefloquine, tribendimidine, oxantel pamoate and doxycycline for the treatment of helminths, and posaconazole and hydroxymethylnitrofurazone for the treatment of protozoa are promising candidates. Therefore, traditional antiprotozoal drugs, which were developed in some cases decades ago, are a valid solution. Herein, we review the current status of traditional anti-helminthic and antiprotozoal drugs in terms of drug targets, mode of action, doses, adverse effects, and parasite resistance to define their suitability for repurposing strategies. Current antiparasitic drugs are not only still viable for the treatment of helminth and protozoan infections but are also important candidates for new pharmacological treatments.

Cyclin-dependent Kinase 8 (CDK8), a member of the CDKs family, has been widely focused owing to investigations of its critical roles in transcription and oncogenesis in recent years. Selective inhibition of CDK8 and its paralog CDK19 offers a novel therapeutic strategy for the treatment of some cancers. Up to now, though many small molecules against CDK8 have been discovered, most of them are discontinued in the preclinical trials due to the low selectivity and poor physicochemical properties. This review mainly summarizes the design strategies of selective CDK8 inhibitors having different chemical scaffolds with the aim to improve the inhibitory activity, selectivity, metabolic stability and solubility. Their corresponding Structure-activity Relationships (SAR) are also reviewed. On the basis of the discussion in this review, we hope more effective, selective and drug-like CDK8 inhibitors will be developed and demonstrate therapeutic values in the near future.

The article entitled “Phytochemicals from Plants to Combat Cardiovascular Disease”, by Hannah R. Vasan-thi, Nitin ShriShri Mal, Dilip Kumar Das, published in Curr. Med. Chem. 2012; 19(14): 224251. https://www.eurekaselect.com/97287/article has been retracted on a complaint of plagiarism with a previously pub-lished article entitled “Resveratrol in cardiovascular health and disease” in the journal Annals of the New York Academy of Sciences as Ann N Y Acad Sci . 2011 Jan;1215:22-33. doi: 10.1111/j.1749-6632.2010.05843.x The authors were informed of this complaint and were requested to give justification on the matter, in their de-fence. However, no reply was received from them in this regard. Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused. The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php.