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Journal of Hematology & Oncology May 2020Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand... (Review)
Review
Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting ~ 50 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for cancer therapy. This article reviews PROTAC-mediated degradation of critical oncoproteins in cancer, particularly those in hematological malignancies. Chemical structures, cellular and in vivo activities, pharmacokinetics, and pharmacodynamics of these PROTACs are summarized. In addition, potential advantages, challenges, and perspectives of PROTAC technology in cancer therapy are discussed.
Topics: Animals; Antineoplastic Agents; Drug Discovery; Humans; Ligands; Molecular Targeted Therapy; Neoplasms; Proteolysis; Ubiquitination
PubMed: 32404196
DOI: 10.1186/s13045-020-00885-3 -
Molecules (Basel, Switzerland) Nov 2022Natural products have been an invaluable and useful source of anticancer agents over the years. Several compounds have been synthesized from natural products by... (Review)
Review
Natural products have been an invaluable and useful source of anticancer agents over the years. Several compounds have been synthesized from natural products by modifying their structures or by using naturally occurring compounds as building blocks in the synthesis of these compounds for various purposes in different fields, such as biology, medicine, and engineering. Multiple modern and costly treatments have been applied to combat cancer and limit its lethality, but the results are not significantly refreshing. Natural products, which are a significant source of new therapeutic drugs, are currently being investigated as potential cytotoxic agents and have shown a positive trend in preclinical research and have prompted numerous innovative strategies in order to combat cancer and expedite the clinical research. Natural products are becoming increasingly important for drug discovery due to their high molecular diversity and novel biofunctionality. Furthermore, natural products can provide superior efficacy and safety due to their unique molecular properties. The objective of the current review is to provide an overview of the emergence of natural products for the treatment and prevention of cancer, such as chemosensitizers, immunotherapeutics, combinatorial therapies with other anticancer drugs, novel formulations of natural products, and the molecular mechanisms underlying their anticancer properties.
Topics: Humans; Biological Products; Antineoplastic Agents; Neoplasms; Drug Discovery
PubMed: 36500466
DOI: 10.3390/molecules27238367 -
Acta Pharmacologica Sinica Oct 2022Pyroptosis, an inflammatory form of lytic cell death, is a type of cell death mediated by the gasdermin (GSDM) protein family. Upon recognizing exogenous or endogenous... (Review)
Review
Pyroptosis, an inflammatory form of lytic cell death, is a type of cell death mediated by the gasdermin (GSDM) protein family. Upon recognizing exogenous or endogenous signals, cells undergo inflammasome assembly, GSDM cleavage, the release of proinflammatory cytokines and other cellular contents, eventually leading to inflammatory cell death. In this review, we discuss the roles of the GSDM family for anti-cancer functions and various antitumor drugs that could activate the pyroptosis pathways.
Topics: Antineoplastic Agents; Cytokines; Inflammasomes; Neoplasm Proteins; Neoplasms; Pyroptosis
PubMed: 35288674
DOI: 10.1038/s41401-022-00887-6 -
European Journal of Clinical... Apr 2021This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug... (Review)
Review
PURPOSE
This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed.
METHODS
A comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted.
RESULTS
OADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy.
CONCLUSION
Sub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window.
Topics: Administration, Oral; Antineoplastic Agents; Drug Monitoring; Humans
PubMed: 33165648
DOI: 10.1007/s00228-020-03014-8 -
International Journal of Molecular... Nov 2020The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay detects DNA breakage by labeling the free 3'-hydroxyl termini. Given that genomic... (Review)
Review
The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay detects DNA breakage by labeling the free 3'-hydroxyl termini. Given that genomic DNA breaks arise during early and late stages of apoptosis, TUNEL staining continues to be widely used as a measure of apoptotic cell death. The advantages of the assay include its relative ease of performance and the broad availability of TUNEL assay kits for various applications, such as single-cell analysis of apoptosis in cell cultures and tissue samples. However, as briefly discussed herein, aside from some concerns relating to the specificity of the TUNEL assay itself, it was demonstrated some twenty years ago that the early stages of apoptosis, detected by TUNEL, can be reversed. More recently, compelling evidence from different biological systems has revealed that cells can recover from even late stage apoptosis through a process called anastasis. Specifically, such recovery has been observed in cells exhibiting caspase activation, genomic DNA breakage, phosphatidylserine externalization, and formation of apoptotic bodies. Furthermore, there is solid evidence demonstrating that apoptotic cells can promote neighboring tumor cell repopulation (e.g., through caspase-3-mediated secretion of prostaglandin E) and confer resistance to anticancer therapy. Accordingly, caution should be exercised in the interpretation of results obtained by the TUNEL and other apoptosis assays (e.g., caspase activation) in terms of apoptotic cell demise.
Topics: Animals; Antineoplastic Agents; Apoptosis; Biological Assay; DNA Breaks; Humans; In Situ Nick-End Labeling; Neoplasms
PubMed: 33260475
DOI: 10.3390/ijms21239090 -
Journal of Hematology & Oncology Jul 2022p53, encoded by the tumor suppressor gene TP53, is one of the most important tumor suppressor factors in vivo and can be negatively regulated by MDM2 through p53-MDM2... (Review)
Review
p53, encoded by the tumor suppressor gene TP53, is one of the most important tumor suppressor factors in vivo and can be negatively regulated by MDM2 through p53-MDM2 negative feedback loop. Abnormal p53 can be observed in almost all tumors, mainly including p53 mutation and functional inactivation. Blocking MDM2 to restore p53 function is a hotspot in the development of anticancer candidates. Till now, nine MDM2 inhibitors with different structural types have entered clinical trials. However, no MDM2 inhibitor has been approved for clinical application. This review focused on the discovery, structural modification, preclinical and clinical research of the above compounds from the perspective of medicinal chemistry. Based on this, the possible defects in MDM2 inhibitors in clinical development were analyzed to suggest that the multitarget strategy or targeted degradation strategy based on MDM2 has the potential to reduce the dose-dependent hematological toxicity of MDM2 inhibitors and improve their anti-tumor activity, providing certain guidance for the development of agents targeting the p53-MDM2 interaction.
Topics: Antineoplastic Agents; Humans; Neoplasms; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53
PubMed: 35831864
DOI: 10.1186/s13045-022-01314-3 -
Journal of Medicinal Chemistry Nov 2022Bicycle toxin conjugates (BTCs) are a promising new class of molecules for targeted delivery of toxin payloads into tumors. Herein we describe the discovery of BT8009, a...
Bicycle toxin conjugates (BTCs) are a promising new class of molecules for targeted delivery of toxin payloads into tumors. Herein we describe the discovery of BT8009, a Nectin-4 targeting BTC currently under clinical evaluation. Nectin-4 is overexpressed in multiple tumor types and is a clinically validated target for selective delivery of cytotoxic payloads. A Nectin-4 targeting bicyclic peptide was identified by phage display, which showed highly selective binding for Nectin-4 but suffered from low plasma stability and poor physicochemical properties. Multiparameter chemical optimization involving introduction of non-natural amino acids resulted in a lead Bicycle that demonstrated high affinity for Nectin-4, good stability in biological matrices, and a much-improved physicochemical profile. The optimized Bicycle was conjugated to the cytotoxin Monomethyl auristatin E via a cleavable linker to give the targeted drug conjugate BT8009, which demonstrates potent anticancer activity in in vivo rodent models.
Topics: Humans; Immunotoxins; Nectins; Bicycling; Neoplasms; Antineoplastic Agents; Cell Adhesion Molecules; Immunoconjugates; Cell Line, Tumor
PubMed: 36204777
DOI: 10.1021/acs.jmedchem.2c00065 -
Bioorganic & Medicinal Chemistry Dec 2020Azaindole structural framework is an integral part of several biologically active natural and synthetic organic molecules; and several FDA approved drugs for various...
Azaindole structural framework is an integral part of several biologically active natural and synthetic organic molecules; and several FDA approved drugs for various diseases. In the last decade, quite a number of literature reports appeared describing the pharmacology, biological activity and therapeutic applications of a variety of azaindole molecules. This prompted the organic and medicinal chemistry community to develop novel synthetic methods for various azaindoles and test them for a bioactivity against a variety of biological targets. Herein, we have summarized the biological activity of therapeutically advanced clinical candidates and several preclinical candidate drugs that contain azaindole structural moiety.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Aza Compounds; Cell Proliferation; Humans; Hypersensitivity; Indoles; Influenza A Virus, H1N1 Subtype; Neoplasms
PubMed: 33161343
DOI: 10.1016/j.bmc.2020.115830 -
Molecules (Basel, Switzerland) Nov 2022Natural products and their derivatives have been shown to be effective drug candidates against various diseases for many years. Over a long period of time, nature has... (Review)
Review
Natural products and their derivatives have been shown to be effective drug candidates against various diseases for many years. Over a long period of time, nature has produced an abundant and prosperous source pool for novel therapeutic agents with distinctive structures. Major natural-product-based drugs approved for clinical use include anti-infectives and anticancer agents. This paper will review some natural-product-related potent anticancer, anti-HIV, antibacterial and antimalarial drugs or lead compounds mainly discovered from 2016 to 2022. Structurally typical marine bioactive products are also included. Molecular modeling, machine learning, bioinformatics and other computer-assisted techniques that are very important in narrowing down bioactive core structural scaffolds and helping to design new structures to fight against key disease-associated molecular targets based on available natural products are considered and briefly reviewed.
Topics: Drug Discovery; Biological Products; Anti-Infective Agents; Antineoplastic Agents; Natural Resources
PubMed: 36500375
DOI: 10.3390/molecules27238280 -
International Journal of Molecular... May 2022Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most... (Review)
Review
Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intracellular transport, inhibit cell proliferation and promote cell death. Because these drugs target biological processes that are essential to all cells, they face an additional challenge when compared to most other drug classes. General toxicity can limit the applicable dose and therefore reduce therapeutic benefits. Photopharmacology aims to avoid these side-effects by introducing compounds that can be applied globally to cells in their inactive form, then be selectively induced to bioactivity in targeted cells or tissue during a defined time window. This review discusses photoswitchable analogues of antimitotic agents that have been developed by combining different photoswitchable motifs with microtubule-stabilizing or microtubule-destabilizing agents.
Topics: Antimitotic Agents; Antineoplastic Agents; Humans; Microtubules; Neoplasms; Vinca Alkaloids
PubMed: 35628467
DOI: 10.3390/ijms23105657