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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 -
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 -
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 -
Molecules (Basel, Switzerland) Feb 2020Cancer is one of the major causes of death worldwide [...].
Cancer is one of the major causes of death worldwide [...].
Topics: Antineoplastic Agents; Biological Products; Humans; Neoplasms
PubMed: 32028725
DOI: 10.3390/molecules25030650 -
Annals of Oncology : Official Journal... Jun 2018
Topics: Antineoplastic Agents; Drug Industry; Humans; Neoplasms; Pharmaceutical Preparations
PubMed: 29648577
DOI: 10.1093/annonc/mdy131 -
Acta Microbiologica Et Immunologica... Aug 2018Fungal toxins are secondary metabolites, in which many of them were mycotoxins, affecting eukaryotic cells with a broad range of structural and functional variety... (Review)
Review
Fungal toxins are secondary metabolites, in which many of them were mycotoxins, affecting eukaryotic cells with a broad range of structural and functional variety contributing to the multitude of their classification. This refers to the harmful genotoxic (mutagenic, teratogenic, and carcinogenic) effects of mycotoxins on the one hand, and their cytocidic and antineoplastic properties on the other hand. This "double edged sword" effect could be utilized against the spread of tumors in older patients when the survival is much more important than the mutagenic side effects. To decide which fungal toxins could be used as combined cytotoxic and antimetastatic agents, mycotoxins were divided into three categories: (a) highly genotoxic (mutagenic, teratogenic, and carcinogenic), (b) adversely toxic, and (c) antitumorigenic agents. Highly cytotoxic mycotoxins with tolerable side effects, combined with an antineoplastic character, could be potential candidates against metastasis. From the structure-function relationship of antimetastatic mycotoxins, only general conclusions have been drawn. The presence of ring structures containing heteroatoms, functional groups, and the cumulative presence of oxygen atoms contributed to the oxidative stress and cytotoxicity of mycotoxins. The preselection of mycotoxins excluded category (a), and only the categories (b) and
Topics: Animals; Antineoplastic Agents; Humans; Mycotoxins; Neoplasms
PubMed: 29552898
DOI: 10.1556/030.65.2018.015 -
Molecules (Basel, Switzerland) Mar 2021It has been an absolute pleasure to be the guest editor of this Special Issue! As the title indicates, the topic is on the advances made against cancer [...].
It has been an absolute pleasure to be the guest editor of this Special Issue! As the title indicates, the topic is on the advances made against cancer [...].
Topics: Antineoplastic Agents; Drug Discovery; Humans; Neoplasms
PubMed: 33804936
DOI: 10.3390/molecules26071821 -
Molecules (Basel, Switzerland) Nov 2021Continuous flow chemistry is by now an established and valued synthesis technology regularly exploited in academic and industrial laboratories to bring about the... (Review)
Review
Continuous flow chemistry is by now an established and valued synthesis technology regularly exploited in academic and industrial laboratories to bring about the improved preparation of a variety of molecular structures. Benefits such as better heat and mass transfer, improved process control and safety, a small equipment footprint, as well as the ability to integrate in-line analysis and purification tools into telescoped sequences are often cited when comparing flow to analogous batch processes. In this short review, the latest developments regarding the exploitation of continuous flow protocols towards the synthesis of anticancer drugs are evaluated. Our efforts focus predominately on the period of 2016-2021 and highlight key case studies where either the final active pharmaceutical ingredient (API) or its building blocks were produced continuously. It is hoped that this manuscript will serve as a useful synopsis showcasing the impact of continuous flow chemistry towards the generation of important anticancer drugs.
Topics: Antineoplastic Agents; Drug Screening Assays, Antitumor; Humans; Technology, Pharmaceutical
PubMed: 34834084
DOI: 10.3390/molecules26226992 -
Cancer Letters Jun 2023Cancer cells adapt to increasing energy and biosynthetic demands by reprogramming their metabolic pathways. Mitochondria are important organelles for the metabolic... (Review)
Review
Cancer cells adapt to increasing energy and biosynthetic demands by reprogramming their metabolic pathways. Mitochondria are important organelles for the metabolic reprogramming of tumor cells. In addition to supplying energy, they play crucial roles in the survival, immune evasion, tumor progression, and treatment resistance of the hypoxic tumor microenvironment (TME) in cancer cells. With the development of the life sciences, scientists have gained an in-depth understanding of immunity, metabolism, and cancer, and numerous studies have emphasized that mitochondria are essential for tumor immune escape and the regulation of immune cell metabolism and activation. Moreover, recent evidence suggests that targeting the mitochondria-related pathway with anticancer drugs can initiate the killing of cancer cells by increasing the ability of cancer cells to be recognized by immune cells, tumor antigen presentation ability, and the anti-tumor function of immune cells. This review discusses the effects of mitochondrial morphology and function on the phenotype and function of immune cells under normal and TME conditions, the effects of mitochondrial changes in tumors and microenvironments on tumor immune escape and immune cell function, and finally focuses on the recent research progress and future challenges of novel anti-tumor immunotherapy strategies targeting mitochondria.
Topics: Humans; Neoplasms; Mitochondria; Antineoplastic Agents; Immunotherapy; Antigens, Neoplasm; Tumor Microenvironment
PubMed: 37172686
DOI: 10.1016/j.canlet.2023.216223 -
Molecules (Basel, Switzerland) Nov 2021Ideally, antineoplastic treatment aims to selectively eradicate cancer cells without causing systemic toxicity. A great number of antineoplastic agents (AAs) are... (Review)
Review
Ideally, antineoplastic treatment aims to selectively eradicate cancer cells without causing systemic toxicity. A great number of antineoplastic agents (AAs) are available nowadays, with well-defined therapeutic protocols. The poor bioavailability, non-selective action, high systemic toxicity, and lack of effectiveness of most AAs have stimulated the search for novel chemotherapy protocols, including technological approaches that provide drug delivery systems (DDS) for gold standard medicines. Nanostructured lipid carriers (NLC) are DDS that contain a core of solid and lipid liquids stabilised by surfactants. NLC have high upload capacity for lipophilic drugs, such as the majority of AAs. These nanoparticles can be prepared with a diversity of biocompatible (synthetic or natural) lipid blends, administered by different routes and functionalised for targeting purposes. This review focused on the research carried out from 2000 to now, regarding NLC formulations for AAs (antimetabolites, antimitotics, alkylating agents, and antibiotics) encapsulation, with special emphasis on studies carried out in vivo. NLC systems for codelivery of AAs were also considered, as well as those for non-classical drugs and therapies (natural products and photosensitisers). NLC have emerged as powerful DDS to improve the bioavailability, targeting and efficacy of antineoplastics, while decreasing their toxic effect in the treatment of different types of cancer.
Topics: Animals; Antineoplastic Agents; Biological Availability; Drug Carriers; Drug Compounding; Humans; Lipids; Nanoparticles; Particle Size; Surface-Active Agents
PubMed: 34834022
DOI: 10.3390/molecules26226929