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.
- Klíčová slova
- Triazine, anticancer, breast cancer, cell line, therapeutic potential., toxicity,
- MeSH
- lidé MeSH
- nádory farmakoterapie MeSH
- protinádorové látky * farmakologie chemie terapeutické užití MeSH
- screeningové testy protinádorových léčiv MeSH
- triaziny * farmakologie chemie terapeutické užití MeSH
- vyvíjení léků metody MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- protinádorové látky * MeSH
- triaziny * 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.
- Klíčová slova
- Glutamine antagonist, LC-MS., biomarker, cancer, formylglycinamide ribonucleotide, formylglycinamidine ribonucleotide, purine synthesis,
- MeSH
- biomarkery farmakologické analýza metabolismus MeSH
- chromatografie kapalinová metody MeSH
- glutamin antagonisté a inhibitory MeSH
- glycin analogy a deriváty analýza metabolismus MeSH
- hmotnostní spektrometrie metody MeSH
- metabolické sítě a dráhy účinky léků MeSH
- myši MeSH
- nádorové biomarkery analýza metabolismus MeSH
- nádory * farmakoterapie metabolismus MeSH
- ribonukleotidy * analýza metabolismus MeSH
- vyvíjení léků metody MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- biomarkery farmakologické MeSH
- glutamin MeSH
- glycin MeSH
- nádorové biomarkery MeSH
- phosphoribosyl-N-formylglycineamide MeSH Prohlížeč
- ribonukleotidy * 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.
- Klíčová slova
- infectious diseases, inhibition, parasites, protease, therapy,
- MeSH
- aspartátové endopeptidasy metabolismus MeSH
- COVID-19 enzymologie metabolismus MeSH
- farmakoterapie COVID-19 * MeSH
- inhibitory proteas farmakologie MeSH
- lidé MeSH
- malárie farmakoterapie enzymologie metabolismus MeSH
- Plasmodium falciparum účinky léků patogenita MeSH
- proteasomový endopeptidasový komplex účinky léků MeSH
- SARS-CoV-2 účinky léků patogenita MeSH
- vyvíjení léků metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- aspartátové endopeptidasy MeSH
- inhibitory proteas MeSH
- plasmepsin MeSH Prohlížeč
- proteasomový endopeptidasový komplex MeSH
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.
- Klíčová slova
- Clinical trials, Drug development, Epigenetics, MYCN, Neuroblastoma, Phase I, Preclinical testing,
- MeSH
- cílená molekulární terapie metody trendy MeSH
- dítě MeSH
- experimentální terapie metody trendy MeSH
- inhibitory proteinkinas izolace a purifikace terapeutické užití MeSH
- kongresy jako téma MeSH
- lékařská onkologie metody organizace a řízení trendy MeSH
- lidé MeSH
- nádory mozku farmakoterapie patologie MeSH
- neuroblastom farmakoterapie patologie MeSH
- objevování léků metody organizace a řízení trendy MeSH
- pediatrie metody organizace a řízení trendy MeSH
- protinádorové látky izolace a purifikace terapeutické užití MeSH
- vyvíjení léků * metody organizace a řízení trendy MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Geografické názvy
- Evropa MeSH
- Názvy látek
- inhibitory proteinkinas MeSH
- protinádorové látky MeSH
The last decade has witnessed developments in the CF drug pipeline which are both exciting and unprecedented, bringing with them previously unconsidered challenges. The Task Force group came together to consider these challenges and possible strategies to address them. Over the last 18 months, we have discussed internally and gathered views from a broad range of individuals representing patient organizations, clinical and research teams, the pharmaceutical industry and regulatory agencies. In this and the accompanying article, we discuss two main areas of focus: i) optimising trial design and delivery for speed/efficiency; ii) drug development for patients with rare CFTR mutations. We propose some strategies to tackle the challenges ahead and highlight areas where further thought is needed. We see this as the start of a process rather than the end and hope herewith to engage the wider community in seeking solutions to improved treatments for all patients with CF.
- MeSH
- buněčné kultury metody MeSH
- cílená molekulární terapie metody normy MeSH
- cystická fibróza * farmakoterapie epidemiologie genetika MeSH
- lidé MeSH
- modulátory membránového transportu farmakologie MeSH
- mutace genetika MeSH
- protein CFTR genetika MeSH
- registrace statistika a číselné údaje MeSH
- schvalování léčiv MeSH
- teranostická nanomedicína metody MeSH
- vyvíjení léků * metody normy MeSH
- zlepšení kvality MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa epidemiologie MeSH
- Názvy látek
- modulátory membránového transportu MeSH
- protein CFTR 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
- buňky Hep G2 MeSH
- HeLa buňky MeSH
- histondeacetylasa 6 antagonisté a inhibitory metabolismus MeSH
- inhibitory histondeacetylas farmakologie terapeutické užití MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- mnohočetný myelom farmakoterapie enzymologie MeSH
- proliferace buněk účinky léků fyziologie MeSH
- protinádorové látky farmakologie terapeutické užití MeSH
- vyvíjení léků metody MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- HDAC6 protein, human MeSH Prohlížeč
- histondeacetylasa 6 MeSH
- inhibitory histondeacetylas MeSH
- protinádorové látky MeSH
