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European Journal of Pharmacology Oct 2014Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II), is a well-known chemotherapeutic drug. It has been used for treatment of numerous human cancers including... (Review)
Review
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II), is a well-known chemotherapeutic drug. It has been used for treatment of numerous human cancers including bladder, head and neck, lung, ovarian, and testicular cancers. It is effective against various types of cancers, including carcinomas, germ cell tumors, lymphomas, and sarcomas. Its mode of action has been linked to its ability to crosslink with the purine bases on the DNA; interfering with DNA repair mechanisms, causing DNA damage, and subsequently inducing apoptosis in cancer cells. However, because of drug resistance and numerous undesirable side effects such as severe kidney problems, allergic reactions, decrease immunity to infections, gastrointestinal disorders, hemorrhage, and hearing loss especially in younger patients, other platinum-containing anti-cancer drugs such as carboplatin, oxaliplatin and others, have also been used. Furthermore, combination therapies of cisplatin with other drugs have been highly considered to overcome drug-resistance and reduce toxicity. This comprehensive review highlights the physicochemical properties of cisplatin and related platinum-based drugs, and discusses its uses (either alone or in combination with other drugs) for the treatment of various human cancers. A special attention is paid to its molecular mechanisms of action, and its undesirable side effects.
Topics: Animals; Antineoplastic Agents; Cisplatin; Drug Therapy, Combination; Humans; Neoplasms
PubMed: 25058905
DOI: 10.1016/j.ejphar.2014.07.025 -
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 -
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 -
Bioconjugate Chemistry Nov 2015
Topics: Animals; Antineoplastic Agents; Click Chemistry; Drug Delivery Systems; Humans; Immunoconjugates; Neoplasms
PubMed: 26577284
DOI: 10.1021/acs.bioconjchem.5b00515 -
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 -
Biomolecules Dec 2021DNA, a natural biological material, has become an ideal choice for biomedical applications, mainly owing to its good biocompatibility, ease of synthesis, modifiability,... (Review)
Review
DNA, a natural biological material, has become an ideal choice for biomedical applications, mainly owing to its good biocompatibility, ease of synthesis, modifiability, and especially programmability. In recent years, with the deepening of the understanding of the physical and chemical properties of DNA and the continuous advancement of DNA synthesis and modification technology, the biomedical applications based on DNA materials have been upgraded to version 2.0: through elaborate design and fabrication of smart-responsive DNA nanodevices, they can respond to external or internal physical or chemical stimuli so as to smartly perform certain specific functions. For tumor treatment, this advancement provides a new way to solve the problems of precise targeting, controllable release, and controllable elimination of drugs to a certain extent. Here, we review the progress of related fields over the past decade, and provide prospects for possible future development directions.
Topics: Antineoplastic Agents; Biosensing Techniques; DNA; Drug Delivery Systems; Humans; Nanostructures; Neoplasms
PubMed: 34944499
DOI: 10.3390/biom11121855 -
Annals of Oncology : Official Journal... Jun 2018
Topics: Antineoplastic Agents; Drug Industry; Humans; Neoplasms; Pharmaceutical Preparations
PubMed: 29648577
DOI: 10.1093/annonc/mdy131 -
Biochemical Pharmacology Jul 2015Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment,...
Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment, moved rapidly through development from bench in 1994 to first approval in 2003. Bortezomib is a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. All of the agents are potent cytotoxics. The disease focus for all the proteasome inhibitors is multiple myeloma. This focus arose from clinical observations made in bortezomib early clinical trials. Later preclinical studies confirmed that multiple myeloma cells were indeed more sensitive to proteasome inhibitors than other tumor cell types. The discovery and development of the proteasome inhibitor class of anticancer agents has progressed through a classic route of serendipity and scientific investigation. These agents are continuing to have a major impact in their treatment of hematologic malignancies and are beginning to be explored as potential treatment agent for non-cancer indications.
Topics: Antineoplastic Agents; Humans; Neoplasms; Proteasome Inhibitors
PubMed: 25935605
DOI: 10.1016/j.bcp.2015.04.008 -
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