Antineoplastic Marine Secondary Metabolites: Drugs, Drug-Candidates Under Clinical Trials, and Scaffolds of Potential Anticancer Activity

Naturally occurring naphthoquinones (NQs) comprising highly reactive small molecules are the subject of increasing attention due to their promising biological activities such as antioxidant, antimicrobial, apoptosis-inducing activities, and especially anticancer activity. Lapachol, lapachone, and napabucasin belong to the NQs and are in phase II clinical trials for the treatment of many cancers. This review aims to provide a comprehensive and updated overview on the biological activities of several new NQs isolated from different species of plants reported from January 2013 to January 2020, their potential therapeutic applications and their clinical significance.

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Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

Current Molecular Pharmacology ◽

10.2174/1874467213666200422090135 ◽

2020 ◽

Vol 13 (4) ◽

pp. 273-294 ◽

Cited By ~ 2

Author(s):

Elahe Zarini-Gakiye ◽

Javad Amini ◽

Nima Sanadgol ◽

Gholamhassan Vaezi ◽

Kazem Parivar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Small Molecules ◽

Clinical Trial Design ◽

Treatment Approaches ◽

Drug Candidates ◽

Novel Treatments ◽

Approved Drugs ◽

Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

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Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920920069 ◽

2020 ◽

Vol 12 ◽

pp. 175883592092006

Author(s):

Hang-Ping Yao ◽

Sreedhar Reddy Suthe ◽

Xiang-Min Tong ◽

Ming-Hai Wang

Keyword(s):

Clinical Trials ◽

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Targeted Therapeutics ◽

Antibody Drug Conjugates ◽

Drug Candidates ◽

Drug Conjugates ◽

Ron Receptor ◽

Antibody Drug

The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

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Pheophorbide a: State of the Art

Marine Drugs ◽

10.3390/md18050257 ◽

2020 ◽

Vol 18 (5) ◽

pp. 257 ◽

Cited By ~ 2

Author(s):

Assunta Saide ◽

Chiara Lauritano ◽

Adrianna Ianora

Keyword(s):

Clinical Trials ◽

Photodynamic Therapy ◽

Anticancer Activity ◽

State Of The Art ◽

Human Cancer ◽

Human Cancer Cell ◽

Pheophorbide A ◽

Human Cancer Cell Lines ◽

Chlorophyll Breakdown ◽

Chlorophyll Derivative

Chlorophyll breakdown products are usually studied for their antioxidant and anti-inflammatory activities. The chlorophyll derivative Pheophorbide a (PPBa) is a photosensitizer that can induce significant anti-proliferative effects in several human cancer cell lines. Cancer is a leading cause of death worldwide, accounting for about 9.6 million deaths, in 2018 alone. Hence, it is crucial to monitor emergent compounds that show significant anticancer activity and advance them into clinical trials. In this review, we analyze the anticancer activity of PPBa with or without photodynamic therapy and also conjugated with or without other chemotherapic drugs, highlighting the capacity of PPBa to overcome multidrug resistance. We also report other activities of PPBa and different pathways that it can activate, showing its possible applications for the treatment of human pathologies.

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Bioactive Secondary Metabolites of the Genus Diaporthe and Anamorph Phomopsis from Terrestrial and Marine Habitats and Endophytes: 2010–2019

Microorganisms ◽

10.3390/microorganisms9020217 ◽

2021 ◽

Vol 9 (2) ◽

pp. 217

Author(s):

Tang-Chang Xu ◽

Yi-Han Lu ◽

Jun-Fei Wang ◽

Zhi-Qiang Song ◽

Ya-Ge Hou ◽

...

Keyword(s):

Secondary Metabolites ◽

Small Molecules ◽

Host Plants ◽

Plant Pathogens ◽

Bioactive Metabolites ◽

Drug Candidates ◽

The Past ◽

Marine Habitats ◽

Bioactive Secondary Metabolites ◽

Unidentified Species

The genus Diaporthe and its anamorph Phomopsis are distributed worldwide in many ecosystems. They are regarded as potential sources for producing diverse bioactive metabolites. Most species are attributed to plant pathogens, non-pathogenic endophytes, or saprobes in terrestrial host plants. They colonize in the early parasitic tissue of plants, provide a variety of nutrients in the cycle of parasitism and saprophytism, and participate in the basic metabolic process of plants. In the past ten years, many studies have been focused on the discovery of new species and biological secondary metabolites from this genus. In this review, we summarize a total of 335 bioactive secondary metabolites isolated from 26 known species and various unidentified species of Diaporthe and Phomopsis during 2010–2019. Overall, there are 106 bioactive compounds derived from Diaporthe and 246 from Phomopsis, while 17 compounds are found in both of them. They are classified into polyketides, terpenoids, steroids, macrolides, ten-membered lactones, alkaloids, flavonoids, and fatty acids. Polyketides constitute the main chemical population, accounting for 64%. Meanwhile, their bioactivities mainly involve cytotoxic, antifungal, antibacterial, antiviral, antioxidant, anti-inflammatory, anti-algae, phytotoxic, and enzyme inhibitory activities. Diaporthe and Phomopsis exhibit their potent talents in the discovery of small molecules for drug candidates.

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Immune Deregulation in Sepsis and Septic Shock: Reversing Immune Paralysis by Targeting PD-1/PD-L1 Pathway

Frontiers in Immunology ◽

10.3389/fimmu.2020.624279 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yuki Nakamori ◽

Eun Jeong Park ◽

Motomu Shimaoka

Keyword(s):

Clinical Trials ◽

T Lymphocytes ◽

Checkpoint Inhibitors ◽

Immune Therapy ◽

Specific Treatment ◽

Multiple Organ ◽

Lymphoid Cells ◽

Immune Checkpoints ◽

Drug Candidates ◽

Immune Paralysis

Sepsis remains a major problem for human health worldwide, thereby manifesting high rates of morbidity and mortality. Sepsis, once understood as a monophasic sustained hyperinflammation, is currently recognized as a dysregulated host response to infection, with both hyperinflammation and immunoparalysis occurring simultaneously from the earliest stages of sepsis, involving multiple organ dysfunctions. Despite the recent progress in the understanding of the pathophysiology underlying sepsis, no specific treatment to restore immune dysregulation in sepsis has been validated in clinical trials. In recent years, treatment for immune checkpoints such as the programmed cell death protein 1/programmed death ligand (PD-1/PD-L) pathway in tumor-infiltrating T-lymphocytes has been successful in the field of cancer immune therapy. As immune-paralysis in sepsis involves exhausted T-lymphocytes, future clinical applications of checkpoint inhibitors for sepsis are expected. In addition, the functions of PD-1/PD-L on innate lymphoid cells and the role of exosomal forms of PD-L1 warrant further research. Looking back on the history of repeatedly failed clinical trials of immune modulatory therapies for sepsis, sepsis must be recognized as a difficult disease entity for performing clinical trials. A major obstacle that could prevent effective clinical trials of drug candidates is the disease complexity and heterogeneities; clinically diagnosed sepsis could contain multiple sepsis subgroups that suffer different levels of hyper-inflammation and immune-suppression in distinct organs. Thus, the selection of appropriate more homogenous sepsis subgroup is the key for testing the clinical efficacy of experimental therapies targeting specific pathways in either hyperinflammation and/or immunoparalysis. An emerging technology such as artificial intelligence (AI) may help to identify an immune paralysis subgroup who would best be treated by PD-1/PD-L1 pathway inhibitors.

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An Empirical Biomarker-based Calculator for Autosomal Recessive Polycystic Kidney Disease The Nieto-Narayan Formula

10.1101/064139 ◽

2016 ◽

Author(s):

Jake A Nieto ◽

Michael A Yamin ◽

Itzhak D. Goldberg ◽

Prakash Narayan

Keyword(s):

Clinical Trials ◽

Kidney Disease ◽

Polycystic Kidney Disease ◽

Imaging Modality ◽

Pediatric Population ◽

Polycystic Kidney ◽

Drug Candidates ◽

Serial Determination ◽

Stage Renal Disease

Autosomal polycystic kidney disease (ARPKD) is associated with progressive enlargement of the kidneys fuelled by the formation and expansion of fluid-filled cysts. The disease is congenital and children that do not succumb to it during the neonatal period will, by age 10 years, more often than not, require nephrectomy+renal replacement therapy for management of both pain and renal insufficiency. Since increasing cystic index (CI; percent of kidney occupied by cysts) drives both renal expansion and organ dysfunction, management of these patients, including decisions such as elective nephrectomy and prioritization on the transplant waitlist, could clearly benefit from serial determination of CI. So also, clinical trials in ARPKD evaluating efficacy of novel drug candidates could benefit from serial determination of CI. Although ultrasound is currently the imaging modality of choice for diagnosis of ARPKD, its utilization for assessing disease progression is highly limited. Magnetic resonance imaging or computed tomography, although more reliable for determination of CI, are expensive, time-consuming and somewhat impractical in the pediatric population. Using a well-established mammalian model of ARPKD, we undertook a big data-like analysis of minimally- or non-invasive serum and urine biomarkers of renal injury/dysfunction to derive a family of equations for estimating CI. We then applied a signal averaging protocol to distil these equations to a single empirical formula for calculation of CI. Such a formula will eventually find use in identifying and monitoring patients at high risk for progressing to end-stage renal disease and aid in the conduct of clinical trials.

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Therapeutic Effectiveness and Safety of Repurposing Drugs for the Treatment of COVID-19: Position Standing in 2021

Frontiers in Pharmacology ◽

10.3389/fphar.2021.659577 ◽

2021 ◽

Vol 12 ◽

Author(s):

Safaet Alam ◽

Taslima Binte Kamal ◽

Md. Moklesur Rahman Sarker ◽

Jin-Rong Zhou ◽

S. M. Abdur Rahman ◽

...

Keyword(s):

Clinical Trials ◽

Case Series ◽

Basic Knowledge ◽

World Health ◽

Current Status ◽

Drug Candidates ◽

Health Organization ◽

Meta Analyses

COVID-19, transmitted by SARS-CoV-2, is one of the most serious pandemic situations in the history of mankind, and has already infected a huge population across the globe. This horrendously contagious viral outbreak was first identified in China and within a very short time it affected the world's health, transport, economic, and academic sectors. Despite the recent approval of a few anti-COVID-19 vaccines, their unavailability and insufficiency along with the lack of other potential therapeutic options are continuing to worsen the situation, with valuable lives continuing to be lost. In this situation, researchers across the globe are focusing on repurposing prospective drugs and prophylaxis such as favipiravir, remdesivir, chloroquine, hydroxychloroquine, ivermectin, lopinavir-ritonavir, azithromycin, doxycycline, ACEIs/ARBs, rivaroxaban, and protease inhibitors, which were preliminarily based on in vitro and in vivo pharmacological and toxicological study reports followed by clinical applications. Based on available preliminary data derived from limited clinical trials, the US National Institute of Health (NIH) and USFDA also recommended a few drugs to be repurposed i.e., hydroxychloroquine, remdesivir, and favipiravir. However, World Health Organization later recommended against the use of chloroquine, hydroxychloroquine, remdesivir, and lopinavir/ritonavir in the treatment of COVID-19 infections. Combining basic knowledge of viral pathogenesis and pharmacodynamics of drug molecules as well as in silico approaches, many drug candidates have been investigated in clinical trials, some of which have been proven to be partially effective against COVID-19, and many of the other drugs are currently under extensive screening. The repurposing of prospective drug candidates from different stages of evaluation can be a handy wellspring in COVID-19 management and treatment along with approved anti-COVID-19 vaccines. This review article combined the information from completed clinical trials, case series, cohort studies, meta-analyses, and retrospective studies to focus on the current status of repurposing drugs in 2021.

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