INTRODUCTION: The widespread importance of the synthesis and modification of anticancer agents has given rise to many numbers of medicinal chemistry programs. In this regard, triazine derivatives have attracted attention due to their remarkable activity against a wide range of cancer cells. This evaluation covers work reports to define the anticancer activity, the most active synthesized compound for the target, the SAR and, when described, the probable MOA besides similarly considered to deliver complete and target-pointed data for the development of types of anti-tumour medicines of triazine derivatives. Triazine scaffold for the development of anticancer analogues. Triazine can also relate to numerous beneficial targets, and their analogues have auspicious in-vitro and in-vivo anti-tumour activity. Fused molecules can improve efficacy, and drug resistance and diminish side effects, and numerous hybrid molecules are beneath diverse stages of clinical trials, so hybrid derivatives of triazine may offer valuable therapeutic involvement for the dealing of tumours. OBJECTIVE: The objective of the recent review was to summarize the recent reports on triazine as well as its analogues with respect to its anticancer therapeutic potential. CONCLUSION: The content of the review would be helpful to update the researchers working towards the synthesis and designing of new molecules for the treatment of various types of cancer disease with the recent molecules that have been produced from the triazine scaffold. Triazine scaffolds based on 1,3,5-triazine considerably boost molecular diversity levels and enable covering chemical space in key medicinal chemistry fields.
- MeSH
- Humans MeSH
- Neoplasms drug therapy MeSH
- Antineoplastic Agents * pharmacology chemistry therapeutic use MeSH
- Drug Screening Assays, Antitumor MeSH
- Triazines * pharmacology chemistry therapeutic use MeSH
- Drug Development methods MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- MeSH
- Image Interpretation, Computer-Assisted methods instrumentation MeSH
- Automation, Laboratory methods instrumentation MeSH
- Microscopy classification methods MeSH
- Drug Discovery * methods MeSH
- High-Throughput Screening Assays methods MeSH
- Combinatorial Chemistry Techniques methods MeSH
- Drug Development methods instrumentation MeSH
- Publication type
- Review MeSH
- MeSH
- Anti-Bacterial Agents * administration & dosage pharmacology classification therapeutic use MeSH
- Drug Resistance, Microbial drug effects MeSH
- Aztreonam pharmacology therapeutic use MeSH
- Bacterial Infections etiology drug therapy microbiology MeSH
- Humans MeSH
- Drug Approval MeSH
- Drug Development methods MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
The work deals with the design, synthesis and biolog-icalactivityofnewcarbamatecholinesteraseinhibitors.Itis focused on selected syntheses of new carbamate deriva-tives, which were tested for their anticholinesterase activi-ty against acetylcholinesterase as well as butyrylcholines-terase. Despite various theories in the pathogenesis of Alz-heimer's disease, drugs that can inhibit these two enzymes still represent the major approach to the treatment of this neurodegenerative disease. Many of the newly synthesized compounds have unique chemical structure. Recently, the approach to the synthesis of new cholinesterase inhibitors has focused on the preparation of potential drugs, contain-ing in their chemical structure fragments of already known drugs, commonly used in the pharmacotherapy of Alzhei-mer's disease, but also other diseases. The aim of prepar-ing these compounds is to affect several biological systems simultaneously. These multipotent compounds have been termed "multi-target-directed ligands"; the molecules of drugs used to treat Alzheimer's disease always contain a pharmacophore acting as a cholinesterase inhibitor, which represents the mainstay of therapy
- MeSH
- Acetylcholinesterase MeSH
- Alzheimer Disease diagnosis drug therapy pathology MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors * chemistry pharmacology therapeutic use MeSH
- Carbamates chemistry therapeutic use MeSH
- Humans MeSH
- Rivastigmine analogs & derivatives therapeutic use MeSH
- Drug Development methods MeSH
- Check Tag
- Humans MeSH
Therapeutic agents with novel mechanisms of action are urgently needed to counter the emergence of drug-resistant infections. Several decades of research into proteases of disease agents have revealed enzymes well suited for target-based drug development. Among them are the three recently validated proteolytic targets: proteasomes of the malarial parasite Plasmodium falciparum, aspartyl proteases of P. falciparum (plasmepsins) and the Sars-CoV-2 viral proteases. Despite some unfulfilled expectations over previous decades, the three reviewed targets clearly demonstrate that selective protease inhibitors provide effective therapeutic solutions for the two most impacting infectious diseases nowadays-malaria and COVID-19.
- MeSH
- Aspartic Acid Endopeptidases metabolism MeSH
- COVID-19 enzymology metabolism MeSH
- COVID-19 Drug Treatment MeSH
- Protease Inhibitors pharmacology MeSH
- Humans MeSH
- Malaria drug therapy enzymology metabolism MeSH
- Plasmodium falciparum drug effects pathogenicity MeSH
- Proteasome Endopeptidase Complex drug effects MeSH
- SARS-CoV-2 drug effects pathogenicity MeSH
- Drug Development methods MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
BACKGROUND: Metabolomic analyses from our group and others have shown that tumors treated with glutamine antagonists (GA) exhibit robust accumulation of formylglycinamide ribonucleotide (FGAR), an intermediate in the de novo purine synthesis pathway. The increase in FGAR is attributed to the inhibition of the enzyme FGAR amidotransferase (FGAR-AT) that catalyzes the ATP-dependent amidation of FGAR to formylglycinamidine ribonucleotide (FGAM). While perturbation of this pathway resulting from GA therapy has long been recognized, no study has reported systematic quantitation and analyses of FGAR in plasma and tumors. OBJECTIVE: Herein, we aimed to evaluate the efficacy of our recently discovered tumor-targeted GA prodrug, GA-607 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate), and demonstrate its target engagement by quantification of FGAR in plasma and tumors. METHODS: Efficacy and pharmacokinetics of GA-607 were evaluated in a murine EL4 lymphoma model followed by global tumor metabolomic analysis. Liquid chromatography-mass spectrometry (LC-MS) based methods employing the ion-pair chromatography approach were developed and utilized for quantitative FGAR analyses in plasma and tumors. RESULTS: GA-607 showed preferential tumor distribution and robust single-agent efficacy in a murine EL4 lymphoma model. While several metabolic pathways were perturbed by GA-607 treatment, FGAR showed the highest increase qualitatively. Using our newly developed sensitive and selective LC-MS method, we showed a robust >80- and >10- fold increase in tumor and plasma FGAR levels, respectively, with GA-607 treatment. CONCLUSION: These studies describe the importance of FGAR quantification following GA therapy in cancer and underscore its importance as a valuable pharmacodynamic marker in the preclinical and clinical development of GA therapies.
- MeSH
- Biomarkers, Pharmacological analysis metabolism MeSH
- Chromatography, Liquid methods MeSH
- Glutamine antagonists & inhibitors MeSH
- Glycine analogs & derivatives analysis metabolism MeSH
- Mass Spectrometry methods MeSH
- Metabolic Networks and Pathways drug effects MeSH
- Mice MeSH
- Biomarkers, Tumor analysis metabolism MeSH
- Neoplasms * drug therapy metabolism MeSH
- Ribonucleotides * analysis metabolism MeSH
- Drug Development methods MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
Nestr.
Významné úspěchy v oblasti nádorové imunoterapie, kterých bylo dosaženo v nedávné době úspěšně doplňují zavedené léčebné metody hematologických malignit. Tyto nové metody jsou založené na použití modifikovaných T lymfocytů, které exprimují arteficielní signalizační molekulu označovanou jako Chimerický antigenní receptor (CAR), která přesměruje specifitu T lymfocytů na povrchové antigeny přítomné na nádorových buňkách. V tomto projektu navrhujeme vývoj metod léčby leukemií a lymfomů pomocí CAR-lymfocytů. Dále navrhujeme vývoj metody selektivní expanze T lymfocytů specifických na viry EBV, HCMV a adenoviry z dárcovských lymfocytů, které by bylo možné použít pro léčbu akutní infekce u pacientů po transplantaci kostní dřeně. Cílem projektu je příprava buněk v GMP-kvalitě a preklinická fáze jejich testování. Předkládaný projekt je plně v souladu s prioritami a cíli “Programu na podporu zdravotnického aplikovaného výzkumu a vývoje” v oblasti 1. Vznik a rozvoj chorob a oblasti 2. Nové diagnostické a terapeutické metody, kde plní dílčí cíle 1.3.1., 1.6.1., 2.5.1. a 2.5.2.; Significant progress in the field of tumor immunotherapy has been recently shown to complement available treatment modalities of hematological malignancies. This novel treatment method is based on the use adoptively transferred T lymphocytes which were modified in vitro prior to transfer to express artificial signaling molecule designated Chimeric Antigen Receptor (CAR) which redirects the specificity of modified lymphocytes to surface antigens expressed by malignant cells. In this project we propose to develop methods for CAR-based therapy of lymphomas and leukemia. Next, we propose to develop methods for selective expansion of T cells specific for EBV, HCMV or adenovirus from donor lymphocytes for the use in patients who received allogeneic stem cell transplantation and as a result of immunosupresion developed acute viral infection. The goal of the project is the manufacture of GMP-grade cells and their pre-clinical testing. Proposed project meets criteria of national programme for the support of applied medical research in Aims 1.3.1., 1.6.1., 2.5.1. a 2.5.2.
- MeSH
- Cell- and Tissue-Based Therapy methods MeSH
- Receptors, Chimeric Antigen therapeutic use MeSH
- Hematologic Neoplasms genetics therapy MeSH
- Immunotherapy methods MeSH
- Humans MeSH
- T-Lymphocytes MeSH
- Drug Development methods MeSH
- Check Tag
- Humans MeSH
- Conspectus
- Patologie. Klinická medicína
- NML Fields
- hematologie a transfuzní lékařství
- onkologie
- NML Publication type
- závěrečné zprávy o řešení grantu AZV MZ ČR
Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy.
- MeSH
- Molecular Targeted Therapy methods trends MeSH
- Child MeSH
- Therapies, Investigational methods trends MeSH
- Protein Kinase Inhibitors isolation & purification therapeutic use MeSH
- Congresses as Topic MeSH
- Medical Oncology methods organization & administration trends MeSH
- Humans MeSH
- Brain Neoplasms drug therapy pathology MeSH
- Neuroblastoma drug therapy pathology MeSH
- Drug Discovery methods organization & administration trends MeSH
- Pediatrics methods organization & administration trends MeSH
- Antineoplastic Agents isolation & purification therapeutic use MeSH
- Drug Development * methods organization & administration trends MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Geographicals
- Europe MeSH
Histone deacetylase 6 (HDAC6) primarily catalyzes the removal of acetyl group from the side chain of acetylated lysine residues in cytoplasmic proteins such as α-tubulin and HSP90. HDAC6 is involved in multiple disease-relevant pathways. Based on the proteolysis targeting chimera strategy, we previously developed the first HDAC6 degrader by tethering a pan-HDAC inhibitor with cereblon (CRBN) E3 ubiquitin ligase ligand. We herein report our new generation of multifunctional HDAC6 degraders by tethering selective HDAC6 inhibitor Nexturastat A with CRBN ligand that can synergize with HDAC6 degradation for the antiproliferation of multiple myeloma (MM). This new class of degraders exhibited improved potency and selectivity for the degradation of HDAC6. After the optimization of the linker length and linking positions, we discovered potent HDAC6 degraders with nanomolar DC50 and promising antiproliferation activity in multiple myeloma (MM) cells.
- MeSH
- Hep G2 Cells MeSH
- HeLa Cells MeSH
- Histone Deacetylase 6 antagonists & inhibitors metabolism MeSH
- Histone Deacetylase Inhibitors pharmacology therapeutic use MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Multiple Myeloma drug therapy enzymology MeSH
- Cell Proliferation drug effects physiology MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Drug Development methods MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
