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Oncology 2022Larotrectinib is a precision oncology treatment for solid tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Larotrectinib efficacy has been...
BACKGROUND
Larotrectinib is a precision oncology treatment for solid tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Larotrectinib efficacy has been evaluated in single-arm basket trials with limited follow-up and sample sizes at the initial regulatory approval due to the rarity of solid tumors with NTRK gene fusion.
OBJECTIVES
We aim to demonstrate that trends in progression-free survival (PFS) and overall survival (OS) in survival data with longer follow-up may be predicted from long-term survival estimates from survival data with shorter follow-up, including predictions for median survival when it is not observed in the trial.
METHODS
Patient-level data were pooled from 3 clinical trials (NCT02122913, NCT02576431, and NCT02637687) using the 2018 and 2020 data cuts for the same subset of pediatric and adult patients. The Weibull distribution was selected for survival models. Survival predictions using 2018 data were compared to 2020 Kaplan-Meier (KM) curves.
RESULTS
A total of 102 patients representing 15 tumor types were included in the analysis, with a mean age of 37 years. When comparing PFS from the 2018 survival prediction to observed 2020 KM data, the 12-month PFS rate was identical (66.6%). The 36-month PFS rate was lower for the 2018 prediction (35.3%) compared to 2020 KM data (44.4%). The median OS had not yet been reached in either data cut but was predicted to be 90 months using the 2018 data. When comparing OS from the 2018 survival prediction to the observed 2020 KM data, the 12-month OS rate was 89.0% and 86.6% and the 48-month OS rate was 67.2% and 63.0%, respectively.
CONCLUSION
Long-term PFS predictions deviated from observed PFS rates due to response differences across tumor types and heavy censoring towards the end of the survival curve. However, for OS, the 48-month survival prediction was consistent with the observed 2020 KM estimate.
Topics: Adolescent; Adult; Child; Clinical Trials as Topic; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Oncogene Proteins, Fusion; Pyrazoles; Pyrimidines; Survival Analysis; Treatment Outcome; Young Adult
PubMed: 34844255
DOI: 10.1159/000519767 -
Molecules (Basel, Switzerland) Jan 2022Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have... (Review)
Review
Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based kinase inhibitors. Pyrazole-possessing kinase inhibitors play a crucial role in various disease areas, especially in many cancer types such as lymphoma, breast cancer, melanoma, cervical cancer, and others in addition to inflammation and neurodegenerative disorders. In this article, we reviewed the structural and biological characteristics of the pyrazole derivatives recently reported as kinase inhibitors and classified them according to their target kinases in a chronological order. We reviewed the reports including pyrazole derivatives as kinase inhibitors published during the past decade (2011-2020).
Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Drug Development; Enzyme Inhibitors; History, 21st Century; Humans; Immune Checkpoint Inhibitors; Models, Molecular; Protein Kinase Inhibitors; Pyrazoles; Signal Transduction; Structure-Activity Relationship
PubMed: 35011562
DOI: 10.3390/molecules27010330 -
Methods (San Diego, Calif.) Jun 2023Small molecules that bind to oligomeric protein species such as membrane proteins and fibrils are of clinical interest for development of therapeutics and diagnostics....
Small molecules that bind to oligomeric protein species such as membrane proteins and fibrils are of clinical interest for development of therapeutics and diagnostics. Definition of the binding site at atomic resolution via NMR is often challenging due to low binding stoichiometry of the small molecule. For fibrils and aggregation intermediates grown in the presence of lipids, we report atomic-resolution contacts to the small molecule at sub nm distance via solid-state NMR using dynamic nuclear polarization (DNP) and orthogonally labelled samples of the protein and the small molecule. We apply this approach to α-synuclein (αS) aggregates in complex with the small molecule anle138b, which is a clinical drug candidate for disease modifying therapy. The small central pyrazole moiety of anle138b is detected in close proximity to the protein backbone and differences in the contacts between fibrils and early intermediates are observed. For intermediate species, the 100 K condition for DNP helps to preserve the aggregation state, while for both fibrils and oligomers, the DNP enhancement is essential to obtain sufficient sensitivity.
Topics: alpha-Synuclein; Pyrazoles; Benzodioxoles; Magnetic Resonance Spectroscopy; Protein Aggregates
PubMed: 37037308
DOI: 10.1016/j.ymeth.2023.04.002 -
Database : the Journal of Biological... Sep 2023The present article describes the building of a small-molecule web server, CBPDdb, employing R-shiny. For the generation of the web server, three compounds were chosen,...
The present article describes the building of a small-molecule web server, CBPDdb, employing R-shiny. For the generation of the web server, three compounds were chosen, namely coumarin, benzothiazole and pyrazole, and their derivatives were curated from the literature. The two-dimensional (2D) structures were drawn using ChemDraw, and the .sdf file was created employing Discovery Studio Visualizer v2017. These compounds were read on the R-shiny app using ChemmineR, and the dataframe consisting of a total of 1146 compounds was generated and manipulated employing the dplyr package. The web server is provided with JSME 2D sketcher. The descriptors of the compounds are obtained using propOB with a filter. The users can download the filtered data in the .csv and .sdf formats, and the entire dataset of a compound can be downloaded in .sdf format. This web server facilitates the researchers to screen plausible inhibitors for different diseases. Additionally, the method used in building the web server can be adapted for developing other small-molecule databases (web servers) in RStudio. Database URL: https://srampogu.shinyapps.io/CBPDdb_Revised/.
Topics: Benzothiazoles; Coumarins; Databases, Factual; Pyrazoles
PubMed: 37702993
DOI: 10.1093/database/baad062 -
Scientific Reports Apr 2023Cancer is one of the leading causes of death worldwide. The increasing prevalence and resistance to chemotherapy is responsible for driving the search of novel molecules...
Cancer is one of the leading causes of death worldwide. The increasing prevalence and resistance to chemotherapy is responsible for driving the search of novel molecules to combat this disease. In search of novel compounds with pro-apoptotic potential, pyrazolo-pyridine and pyrazolo-naphthyridine derivatives were investigated against cervical cancer (HeLa) and breast cancer (MCF-7) cells. The anti-proliferative activity was determined through the MTT assay. Potent compounds were then analyzed for their cytotoxic and apoptotic activity through a lactate dehydrogenase assay and fluorescence microscopy after propidium iodide and DAPI staining. Flow cytometry was used to determine cell cycle arrest in treated cells and pro-apoptotic effect was verified through measurement of mitochondrial membrane potential and activation of caspases. Compounds 5j and 5k were found to be most active against HeLa and MCF-7 cells, respectively. G0/G1 cell cycle arrest was observed in treated cancer cells. Morphological features of apoptosis were also confirmed, and an increased oxidative stress indicated the involvement of reactive oxygen species in apoptosis. The compound-DNA interaction studies demonstrated an intercalative mode of binding and the comet assay confirmed the DNA damaging effects. Finally, potent compounds demonstrated a decrease in mitochondrial membrane potential and increased levels of activated caspase-9 and -3/7 confirmed the induction of apoptosis in treated HeLa and MCF-7 cells. The present work concludes that the active compounds 5j and 5k may be used as lead candidates for the development of lead drug molecules against cervical and breast cancer.
Topics: Female; Humans; Breast Neoplasms; Cell Cycle Checkpoints; Apoptosis; Caspases; Antineoplastic Agents; MCF-7 Cells; Reactive Oxygen Species; Pyrazoles; Pyridines; Naphthyridines; Cell Proliferation; Cell Line, Tumor
PubMed: 37005457
DOI: 10.1038/s41598-023-32489-5 -
Disease Models & Mechanisms Oct 2022Manipulating firing-rate neuronal homeostasis, which enables neurons to regulate their intrinsic excitability, offers an attractive opportunity to prevent seizures....
Manipulating firing-rate neuronal homeostasis, which enables neurons to regulate their intrinsic excitability, offers an attractive opportunity to prevent seizures. However, to date, no drug-based interventions have been reported that manipulate this type of neuronal homeostatic mechanism. Here, we used a combination of Drosophila and mouse, and, in the latter, both a pentylenetetrazole (PTZ)-induced seizure model and an electrically induced seizure model for refractory seizures to evaluate the anticonvulsant efficacy of a novel class of anticonvulsant compounds, based on 4-tert-butyl-benzaldehyde (4-TBB). The mode of action included increased expression of the firing rate homeostatic regulator Pumilio (PUM). Knockdown of pum expression, in Drosophila, blocked anticonvulsive effects of 4-TBB, while analysis of validated PUM targets in mouse brain revealed significant reductions following exposure to this compound. A structure-activity study identified the active parts of the molecule and, further, showed that the pyrazole analogue demonstrates highest efficacy, being active against both PTZ-induced and electrically induced seizures. This study provides a proof of principle that anticonvulsant effects can be achieved through regulation of firing rate neuronal homeostasis and identifies a possible chemical compound for future development.
Topics: Animals; Anticonvulsants; Benzaldehydes; Drosophila; Homeostasis; Mice; Neurons; Pentylenetetrazole; Pyrazoles; Seizures
PubMed: 36073607
DOI: 10.1242/dmm.049703 -
European Journal of Pharmaceutical... Jan 2022The development of new COX-2 inhibitors with analgesic and anti-inflammatory efficacy as well as minimal gastrointestinal, renal and cardiovascular toxicity, is of vital...
The development of new COX-2 inhibitors with analgesic and anti-inflammatory efficacy as well as minimal gastrointestinal, renal and cardiovascular toxicity, is of vital importance to patients suffering from chronic course pain and inflammatory conditions. This study aims at evaluating the therapeutic activity and adverse drug reactions associated with the use of the newly synthesized pyrazole derivative, compound AD732, E-4-[3-(4-methylphenyl)-5-hydroxyliminomethyl-1H-pyrazol-1-yl]benzenesulfonamide, as compared to indomethacin and celecoxib as standard agents. Anti-inflammatory activity was assessed using carrageenan-induced rat paw edema and cotton pellet granuloma tests; formalin-induced hyperalgesia and hot plate tests were done to study analgesic activity. In vitro tests to determine COX-1/COX-2 selectivity and assessment of renal and gastric toxicity upon acute exposure to AD732 were also conducted. Compound AD732 exhibited promising results; higher anti-inflammatory and analgesic effects compared to standard agents, coupled with the absence of ulcerogenic effects and minimal detrimental effects on renal function. Additionally, compound AD732 was a less potent inhibitor of COX-2 in vitro than celecoxib, which may indicate lower potential cardiovascular toxicity. It may be concluded that compound AD732 appears to be a safer and more effective molecule with promising potential for the management of pain and inflammation.
Topics: Analgesics; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Edema; Pyrazoles; Rats; Rats, Wistar
PubMed: 34818572
DOI: 10.1016/j.ejps.2021.106080 -
ChemMedChem Nov 2021Inhibition of membrane-bound pyrophosphatase (mPPase) with small molecules offer a new approach in the fight against pathogenic protozoan parasites. mPPases are absent...
Inhibition of membrane-bound pyrophosphatase (mPPase) with small molecules offer a new approach in the fight against pathogenic protozoan parasites. mPPases are absent in humans, but essential for many protists as they couple pyrophosphate hydrolysis to the active transport of protons or sodium ions across acidocalcisomal membranes. So far, only few nonphosphorus inhibitors have been reported. Here, we explore the chemical space around previous hits using a combination of screening and synthetic medicinal chemistry, identifying compounds with low micromolar inhibitory activities in the Thermotoga maritima mPPase test system. We furthermore provide early structure-activity relationships around a new scaffold having a pyrazolo[1,5-a]pyrimidine core. The most promising pyrazolo[1,5-a]pyrimidine congener was further investigated and found to inhibit Plasmodium falciparum mPPase in membranes as well as the growth of P. falciparum in an ex vivo survival assay.
Topics: Dose-Response Relationship, Drug; Humans; Molecular Structure; Pyrazoles; Pyrimidines; Pyrophosphatases; Structure-Activity Relationship
PubMed: 34459148
DOI: 10.1002/cmdc.202100392 -
Journal of Medical Virology Apr 2022The benefits of baricitinib in coronavirus disease-2019 are inadequately defined. We performed a systematic review and meta-analysis of studies of baricitinib to... (Meta-Analysis)
Meta-Analysis
The benefits of baricitinib in coronavirus disease-2019 are inadequately defined. We performed a systematic review and meta-analysis of studies of baricitinib to determine its clinical efficacy and adverse events in patients with COVID-19. Databases were searched from their inception to September 5, 2021. The primary outcome was the coefficient of mortality. We also compared secondary indicators and adverse events between baricitinib treatment and placebo or other treatments. Twelve studies of 3564 patients were included and assessed qualitatively (modified Jadad and Newcastle-Ottawa Scale scores). Baricitinib effectively improved the mortality rate (relative risk of mortality = 0.56; 95% confidence interval: 0.46-0.69; p < 0.001; I = 2%), and this result was unchanged by subgroup analysis. Baricitinib improved intensive care unit admission, the requirement for invasive mechanical ventilation, and improved the oxygenation index. Data from these studies also showed that baricitinib slightly reduced the risk of adverse events. Regarding the choice of the drug dosage of baricitinib, the high-dose group appeared to have additional benefits for clinical efficacy. Our study shows that baricitinib may be a promising, safe, and effective anti-severe acute respiratory syndrome-coronavirus-2 drug candidate, with the advantages of low cost, easy production, and convenient storage.
Topics: Azetidines; COVID-19; Dose-Response Relationship, Drug; Humans; Purines; Pyrazoles; SARS-CoV-2; Sulfonamides; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 34846766
DOI: 10.1002/jmv.27482 -
International Journal of Molecular... Mar 2023Multi-drug resistant bacterial strains (MDR) have become an increasing challenge to our health system, resulting in multiple classical antibiotics being clinically...
Multi-drug resistant bacterial strains (MDR) have become an increasing challenge to our health system, resulting in multiple classical antibiotics being clinically inactive today. As the de-novo development of effective antibiotics is a very costly and time-consuming process, alternative strategies such as the screening of natural and synthetic compound libraries is a simple approach towards finding new lead compounds. We thus report on the antimicrobial evaluation of a small collection of fourteen drug-like compounds featuring indazoles, pyrazoles and pyrazolines as key heterocyclic moieties whose synthesis was achieved in continuous flow mode. It was found that several compounds possessed significant antibacterial potency against clinical and MDR strains of the and genera, with the lead compound () reaching MIC values of 4 µg/mL on those species. In addition, time killing experiments performed on compound on MDR strains highlight its activity as bacteriostatic. Additional evaluations regarding the physiochemical and pharmacokinetic properties of the most active compounds are reported and showcased, promising drug-likeness, which warrants further explorations of the newly identified antimicrobial lead compound.
Topics: Pyrazoles; Indazoles; Structure-Activity Relationship; Anti-Infective Agents; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 36982392
DOI: 10.3390/ijms24065319