Current Medicinal Chemistry - Volume 29, Issue 15, 2022

Platinum (Pt) drugs, including cisplatin, are widely used for the treatment of solid tumors. Despite the clinical success, side effects and occurrence of resistance represent major limitations to the use of clinically available Pt drugs. To overcome these problems, a variety of derivatives have been designed and synthetized. Here, we summarize the recent progress in the development of Pt(II) and Pt(IV) complexes with bioactive ligands. The development of Pt(II) and Pt(IV) complexes with targeting molecules, clinically available agents, and other bioactive molecules is an active field of research. Even if none of the reported Pt derivatives has been yet approved for clinical use, many of these compounds exhibit promising anticancer activities with an improved pharmacological profile. Thus, planning hybrid compounds can be considered as a promising approach to improve the available Pt-based anticancer agents and to obtain new molecular tools to deepen the knowledge of cancer progression and drug resistance mechanisms.

Background: Entrectinib is a highly potent ATP-competitive and selective inhibitor of tyrosine kinases - Trk A B C, ALK, and ROS1. It was developed by Roche and initially approved in Japan in 2019 to treat pediatric and adult patients with NTRK fusionpositive, recurrent, or advanced solid tumors. In August 2019, entrectinib received accelerated approval by the U.S FDA for this indication. It is also the first FDA-approved drug designed to target both NTRK and ROS1. Objective: We aim to summarize recent studies related to the synthesis, mechanism of action, and clinical trials of the newly approved selective tyrosine kinase inhibitor entrectinib. Methods: We conduct a literature review of the research studies on the new highly-potent small-molecule entrectinib. Conclusion: Entrectinib, based on three clinical studies (ALKA, STARTRK-1, and STARTRK-2), was well tolerated, with a manageable safety profile. It induced clinically meaningful responses in recurrent or advanced solid tumors associated with NTRK fusion- positive or ROS1+ NSCLC. It demonstrated substantial efficacy in patients with CNS metastases.

Kallikrein 7 (KLK7) is a secreted serine protease with chymotrypsic protease activity. Abnormally high expression of KLK7 is closely related to the occurrence and development of various types of cancer. Therefore, KLK7 has been identified as a potential target for cancer drug development design in recent years. KLK7 mediates various biological and pathological processes in tumorigenesis, including cell proliferation, migration, invasion, angiogenesis, and cell metabolism, by hydrolyzing a series of substrates such as membrane proteins, extracellular matrix proteins, and cytokines. This review mainly introduces the downstream cell signaling pathways involved in the activation of KLK7 and its substrate-related proteins. This review will not only help us to better understand the mechanisms of KLK7 in regulating biological and pathological processes of cancer cells but also lay a solid foundation for the design of inhibitors targeting KLK7.

Autism is a neurodevelopmental disorder belonging to the autism spectrum disorder (ASD). In ASDs, the individuals show substantial impairments in social communication, repetitive behaviours, and sensory behaviours deficits in the early stages of their life. Globally, the prevalence of autism is estimated to be less than 1%, especially in high- -income countries. In recent decades, there has been a drastic increase in the incidence of ASD, which has put ASD into the category of epidemics. Presently, two US Food and Drug Administration-approved drugs, aripiprazole and risperidone, are used to treat symptoms of agitation and irritability in autistic children. However, to date, no medication has been found to treat the core symptoms of ASD. The adverse side effects of conventional medicine and limited treatment options have led families of autistic children to turn to complementary and alternative medicine (CAM) treatments, which are perceived as relatively safe compared to conventional medicine. Recently N, N-dimethylglycine (DMG), a dietary supplement, has emerged as a useful supplement to improve the mental and physical state of children with ASD. The current review discusses ASD, the prevalence of ASD, the CAM approach, and the efficacy of CAM treatment in children with ASD. Moreover, it highlights the chemistry, pharmacological effect, and clinical studies of DMG, highlighting its potential for improving the lifestyle of children with ASD.

Hyperinsulinism-hyperammonemia syndrome (HHS) is a rare disease characterized by recurrent hypoglycemia and persistent elevation of plasma ammonia, and it can lead to severe epilepsy and permanent brain damage. It has been demonstrated that functional mutations of glutamate dehydrogenase (GDH), an enzyme in the mitochondrial matrix, are responsible for the HHS. Thus, GDH has become a promising target for the small molecule therapeutic intervention of HHS. Several medicinal chemistry studies are currently aimed at GDH, however, to date, none of the compounds reported has been entered clinical trials. This perspective summarizes the progress in the discovery and development of GDH inhibitors, including the pathogenesis of HHS, potential binding sites, screening methods, and research models. Future therapeutic perspectives are offered to provide a reference for discovering potent GDH modulators and encourage additional research that will provide more comprehensive guidance for drug development.

Background: The COVID-19 pandemic demanded a global effort towards quickly developing safe and effective vaccines against SARS-CoV-2. Objective: This review aimed to discuss the main vaccines available, their mechanisms of action, results of clinical trials, and epidemiological behavior. The implications of viral variants were also debated. Methods: A non-systematic literature review was performed between February and March 2021 by searching the Pubmed, Scopus, and SciELO databases, using different combinations of the following terms: "vaccines", "clinical trials" , "SARS-CoV-2", "Coronavirus", "COVID-19", "mechanisms of action". Data regarding clinical trials of SARS-CoV-2 vaccines and epidemiological information were also searched. Results: The mechanisms of action included vector-virus, mRNA and inactivated virus vaccines. The vaccines showed positive results in phases 2/3 clinical trials. The efficacy of the mRNA 1273 and of mRNA BNT 162b2 vaccines were 94.1% and 95%, respectively. The effectiveness of the ChAdOx1 nCoV-19 vaccine varied according to the scheme, with an overall value of 70.4%. The Gam-COVID-Vac vaccine had an efficacy of 91.6%. Regarding the Ad26.COV2.S vaccine, 99% or more of seroconversion was observed in all subgroups 29 days after vaccination. The CoronaVac vaccine induced an immune response in 92% of the volunteers receiving 3ug and in 98% with 6ug, in comparison to 3% in the placebo group. Conclusion: Global efforts have resulted in vaccines being available in record time, with good safety and immunogenicity profile. However, only long-term studies can provide more information on the duration of immunity and the need for additional doses.

Fast and inexpensive virus identification protocols are of paramount value to hinder the increase of pandemic diseases, minimize economic and social damages, and expedite proper clinical rehabilitation. Until now, various biosensors have been developed for the identification of pathogenic particles. But, they offer many limitations. Nanotechnology overcomes these difficulties and allows a direct identification of pathogenic species in real-time. Among them, nanomaterial based-colorimetric sensing approach for identifying pathogenic viruses by the naked eye has attracted much awareness because of their simplicity, speed, and low cost. In this review, the latest tendencies and advancements used in detecting pathogenic viruses using colorimetric concepts, are overviewed. We focus on and reconsider the use of distinctive nanomaterials such as metal nanoparticles, carbon nanotubes, graphene oxide, and conducting polymer for the formation of colorimetric pathogenic virus sensors.

Background: The major hurdles for successful cancer treatment are drug resistance and invasiveness developed by breast cancer stem cells (BCSC). Objective: As these two processes are highly energy-dependent, the identification of the main ATP supplier required for stem cell viability may result advantageous in the design of new therapeutic strategies to deter malignant carcinomas. Methods: The energy metabolism (glycolysis and oxidative phosphorylation, OxPhos) was systematically analyzed by assessing relevant protein contents, enzyme activities, and pathway fluxes in BCSC. Once identified as the main ATP supplier, selective energy inhibitors and canonical breast cancer drugs were used to block stem cell viability and metastatic properties. Results: OxPhos and glycolytic protein contents, as well as HK and LDH activities were several times higher in BCSC than in their parental line, MCF-7 cells. However, CS, GDH, COX activities, and both energy metabolism pathway fluxes were significantly lower (38-86%) in BCSC than in MCF-7 cells. OxPhos was the main ATP provider (>85%) in BCSC. Accordingly, oligomycin (a specific and potent canonical OxPhos inhibitor) and other non-canonical drugs with inhibitory effect on OxPhos (celecoxib, dimethylcelecoxib) significantly decreased BCSC viability, levels of epithelial-mesenchymal transition proteins, invasiveness, and induced ROS over-production, with IC50 values ranging from 1 to 20 μM in 24 h treatment. In contrast, glycolytic inhibitors (gossypol, iodoacetic acid, 3-bromopyruvate, 2-deoxyglucose) and canonical chemotherapeutic drugs (paclitaxel, doxorubicin, cisplatin) were much less effective against BCSC viability (IC50> 100 μM). Conclusion: These results indicated that the use of some NSAIDs may be a promising alternative therapeutic strategy to target BCSC.

Background: Chronic infection with hepatitis C virus (HCV) is among the major causes of hepatic fibrosis, cirrhosis, as well as hepatocellular carcinoma (HCC), and it is associated with a significant risk of developing lymphoproliferative disorders. The rate of clinical disease progression is variable depending on multiple host and viral factors, including immune response. Methods: To perform a comprehensive epitope mapping of anti-HCV antibodies in patients suffering from HCV-related liver or lymphoproliferative diseases, we analyzed clinical samples on a peptide microarray platform made of 5952 overlapping 15-mer synthetic peptides derived from the whole HCV proteome. We evaluated the antibody profile of 71 HCV-positive patients diagnosed with HCC, mixed cryoglobulinemia (MC), and HCV chronic infection. Antibody reactivity against virus peptides was detected in all HCVpositive patients. Importantly, the signal amplitude varied significantly within and between diverse patient groups. Results: Antibody reactivity against C peptides were found generally low in HCV chronically infected asymptomatic subjects and increasingly high in HCC and MC patients. Moreover, we found a statistically significant higher IgG response in HCC and MC patients against specific domains of HCV C, E2, NS3, NS4A, NS4B, NS5A, and p7 compared to HCV-positive subjects. Conclusion: In conclusion, our data suggest that immune response against specific HCV protein domains may represent useful biomarkers of disease progression among HCVpositive patients and suggest that peptide microarrays are good tools for the screening of immunotherapy targets in preclinical HCV research.