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Journal of Comparative Effectiveness... Oct 2022To extrapolate clinical trial results to estimate and compare expected progression-free and overall life years (LYs) and quality-adjusted LYs (QALYs) for larotrectinib...
To extrapolate clinical trial results to estimate and compare expected progression-free and overall life years (LYs) and quality-adjusted LYs (QALYs) for larotrectinib and entrectinib in patients with colorectal cancer (CRC), soft tissue sarcoma (STS) and brain metastases prior to treatment with larotrectinib or entrectinib. A naive direct comparison of larotrectinib versus entrectinib was made using partitioned survival modeling methods from clinical trial data. Larotrectinib resulted in an additional 1.58 LYs (1.17 QALYs), 5.81 LYs (2.02 QALYs) and 1.01 LYs in CRC, STS and baseline brain metastases, respectively, compared with entrectinib. Larotrectinib provided life expectancy and QALY gains compared with entrectinib. Additional studies will be beneficial as more patients are treated and survival data develop to better inform comparative effectiveness results.
Topics: Benzamides; Brain Neoplasms; Clinical Trials as Topic; Gene Fusion; Humans; Indazoles; Pyrazoles; Pyrimidines
PubMed: 35993247
DOI: 10.2217/cer-2021-0247 -
Scientific Reports Apr 2023Dual-tail strategy has been successfully utilized in the development of novel carbonic anhydrase IX (CA IX) inhibitors. Herein we adopted this approach in the design and...
Dual-tail strategy has been successfully utilized in the development of novel carbonic anhydrase IX (CA IX) inhibitors. Herein we adopted this approach in the design and synthesis of a series of novel pyridine sulfonamide-pyrazole hybrid scaffold mimicking dual-tail inhibitors of CA IX. A library of 15 compounds was synthesized and assessed for their potential cytotoxic effects against colorectal cancer cells. Compounds 3, and 11 induced potential cytotoxic effects against the three cancer cell lines (HCT-116, HT-29, and SW-620) with ICs' of 45.88, 28.27, and 16.57 uM, 25.01, 8.99, and 3.27 µM, respectively. Both compounds induced cellular apoptosis on HCT-116 and SW-620 cells, while compound 3 induced necrosis as well. In addition, both compounds induced cell cycle arrest on G0/G1, and S phases. Also, compound 11 showed potential autophagy induction on both colon cancer cell lines (HCT-116, and HT-29), and a little bit on metastatic type. Both compounds were less cytotoxic than the reference drug on normal epithelial cell. The migration rates of HCT-116 and the metastatic one SW-620 were reduced by both compounds. Finally, molecular docking of compounds 3 and 11 into the active site of CA IX confirmed in vitro inhibitory activity for both compounds.
Topics: Humans; Structure-Activity Relationship; Molecular Docking Simulation; Carbonic Anhydrase IX; Sulfonamides; Antineoplastic Agents; Colonic Neoplasms; Apoptosis; Pyrazoles; Molecular Structure; Cell Proliferation
PubMed: 37031294
DOI: 10.1038/s41598-023-32820-0 -
Journal of Cellular and Molecular... Jan 2021Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and... (Clinical Trial)
Clinical Trial
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and steroids, many patients can recover from severe CRS. However, some patients are refractory to steroids and develop life-threatening consequences. Ruxolitinib is an oral JAKs inhibitor and promising drug in inflammatory diseases. In this pilot study, we evaluate the efficacy of Ruxolitinib in CRS. Of 14 r/r B-ALL children who received CD19 or CD22 CAR T cell therapies, 4 patients developed severe (≥grade 3) CRS with symptoms that were not alleviated with high-dose steroids and thus received ruxolitinib. Rapid resolution of CRS symptoms was observed in 4 patients after ruxolitinib treatment. Serum cytokines significantly decreased after ruxolitinib intervention. All patients achieved complete remission on day 30 after infusion, and we could still detect CAR T expansion in vivo despite usage of ruxolitinib. There were no obvious adverse events related to ruxolitinib. In vitro assays revealed that ruxolitinib could dampen CAR T expansion and cytotoxicity, suggesting that the timing and dosage of ruxolitinib should be carefully considered to avoid dampening anti-leukaemia response. Our results suggest that ruxolitinib is active and well tolerated in steroid-refractory and even life-threatening CRS.
Topics: Adolescent; Cell Proliferation; Child; Child, Preschool; Cytokine Release Syndrome; Cytokines; Dexamethasone; Female; Humans; Immunotherapy, Adoptive; Male; Nitriles; Pilot Projects; Pyrazoles; Pyrimidines; Steroids; Treatment Outcome
PubMed: 33314568
DOI: 10.1111/jcmm.16176 -
Annals of Medicine Dec 2022A series of -(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles was synthesised and screened for their potential to inhibit kinases and exhibit anticancer activity...
A series of -(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles was synthesised and screened for their potential to inhibit kinases and exhibit anticancer activity against primary patient-derived glioblastoma 2D cells and 3D neurospheres. A collection of 10 compounds was evaluated against glioma cell lines, with compound exhibiting promising glioma growth inhibitory properties. Compound was screened against 139 purified kinases and exhibited low micromolar activity against kinase AKT2/PKBβ. AKT signalling is one of the main oncogenic pathways in glioma and is often targeted for novel therapeutics. Indeed, AKT2 levels correlated with glioma malignancy and poorer patient survival. Compound inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells and exhibited potent EC against glioblastoma cell lines. Although exhibiting potency against glioma cells, exhibited significantly less cytotoxicity against non-cancerous cells even at fourfold-fivefold the concentration. Herein we establish a novel biochemical kinase inhibitory function for -(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles and further report their anti-glioma activity for the first time.KEY MESSAGEAnti-glioma pyrano[2,3-c]pyrazole inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells. also displayed PKBβ/AKT2 inhibitory activity. is nontoxic towards non-cancerous cells.
Topics: Glioblastoma; Humans; Proto-Oncogene Proteins c-akt; Pyrazoles
PubMed: 36120909
DOI: 10.1080/07853890.2022.2123559 -
Molecules (Basel, Switzerland) Jul 2022Pyrazole and its derivatives are considered a privileged -heterocycle with immense therapeutic potential. Over the last few decades, the pot, atom, and step economy... (Review)
Review
Pyrazole and its derivatives are considered a privileged -heterocycle with immense therapeutic potential. Over the last few decades, the pot, atom, and step economy (PASE) synthesis of pyrazole derivatives by multicomponent reactions (MCRs) has gained increasing popularity in pharmaceutical and medicinal chemistry. The present review summarizes the recent developments of multicomponent reactions for the synthesis of biologically active molecules containing the pyrazole moiety. Particularly, it covers the articles published from 2015 to date related to antibacterial, anticancer, antifungal, antioxidant, α-glucosidase and α-amylase inhibitory, anti-inflammatory, antimycobacterial, antimalarial, and miscellaneous activities of pyrazole derivatives obtained exclusively via an MCR. The reported analytical and activity data, plausible synthetic mechanisms, and molecular docking simulations are organized in concise tables, schemes, and figures to facilitate comparison and underscore the key points of this review. We hope that this review will be helpful in the quest for developing more biologically active molecules and marketed drugs containing the pyrazole moiety.
Topics: Anti-Bacterial Agents; Antifungal Agents; Chemistry, Pharmaceutical; Molecular Docking Simulation; Pyrazoles; alpha-Glucosidases
PubMed: 35897899
DOI: 10.3390/molecules27154723 -
Molecules (Basel, Switzerland) May 2021Pyrazolo[1,5-]pyrimidine () derivatives are an enormous family of -heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great... (Review)
Review
Pyrazolo[1,5-]pyrimidine () derivatives are an enormous family of -heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great deal of attention in material science recently due to their significant photophysical properties. Consequently, various researchers have developed different synthesis pathways for the preparation and post-functionalization of this functional scaffold. These transformations improve the structural diversity and allow a synergic effect between new synthetic routes and the possible applications of these compounds. This contribution focuses on an overview of the current advances (2015-2021) in the synthesis and functionalization of diverse pyrazolo[1,5-]pyrimidines. Moreover, the discussion highlights their anticancer potential and enzymatic inhibitory activity, which hopefully could lead to new rational and efficient designs of drugs bearing the pyrazolo[1,5-]pyrimidine core.
Topics: Animals; Antineoplastic Agents; Catalysis; Enzyme Inhibitors; Humans; Pyrazoles; Pyrimidines
PubMed: 34063043
DOI: 10.3390/molecules26092708 -
Scientific Reports Jun 2023Microbial infections are currently a widespread disease in hospitals and community health centres and are a major cause of death worldwide. In pursuit of searching new...
Microbial infections are currently a widespread disease in hospitals and community health centres and are a major cause of death worldwide. In pursuit of searching new antimicrobial agents, coumarin linked to thiazoles, pyridines and pyrazoles have been developed and evaluated for their antimicrobial properties against two Gram + bacteria, two Gram - bacteria as well as two fungi. Some of the prepared coumarins displayed high to moderate activity against the tested microorganisms with respect to the reference drugs. However, compound 3 exhibited antimicrobial effect equal to the reference drug Ciprofloxacin for Gram - baceria Enterobacter cloacae. Compound 12 was found to be the most potent compound against Bacillus pumilis with MIC of 7.69 (µmol/ml). Compounds 3, 4 and 12 showed remarkable activity against Streptococcus faecalis with MIC of 14.34, 3.67 and 15.36 (µmol/ml), respectively. Regarding Escherichia coli, most compounds recorded high to moderate MIC values (4.73-45.46 µmol/ml). Moreover, in case of E. cloacae compound 9 was the most potent compound with MIC value of 22.76 (µmol/ml).
Topics: Anti-Bacterial Agents; Molecular Structure; Thiazoles; Pyrazoles; Pyridines; Microbial Sensitivity Tests; Anti-Infective Agents; Coumarins
PubMed: 37336955
DOI: 10.1038/s41598-023-36705-0 -
JCO Precision Oncology May 2023
Topics: Humans; Pyrazoles; Receptor, trkA; Protein Kinase Inhibitors; Mutation
PubMed: 37262390
DOI: 10.1200/PO.22.00697 -
Scientific Reports Jul 2020Parkinson's disease (PD) and Alzheimer's disease (AD) are common neurodegenerative disorders of the elderly and, therefore, affect a growing number of patients...
Parkinson's disease (PD) and Alzheimer's disease (AD) are common neurodegenerative disorders of the elderly and, therefore, affect a growing number of patients worldwide. Both diseases share, as a common hallmark, the accumulation of characteristic protein aggregates, known as Lewy bodies (LB) in PD, and neurofibrillary tangles in AD. LBs are primarily composed of misfolded α-synuclein (aSyn), and neurofibrillary tangles are primarily composed of tau protein. Importantly, upon pathological evaluation, most AD and PD/Lewy body dementia cases exhibit mixed pathology, with the co-occurrence of both LB and neurofibrillary tangles, among other protein inclusions. Recent studies suggest that both aSyn and tau pathology can spread and propagate through neuronal connections. Therefore, it is important to investigate the mechanisms underlying aggregation and propagation of these proteins for the development of novel therapeutic strategies. Here, we assessed the effects of different pharmacological interventions on the aggregation and internalization of tau and aSyn. We found that anle138b and fulvic acid decrease aSyn and tau aggregation, that epigallocatechin gallate decreases aSyn aggregation, and that dynasore reduces tau internalization. Establishing the effects of small molecules with different chemical properties on the aggregation and spreading of aSyn and tau will be important for the development of future therapeutic interventions.
Topics: Alzheimer Disease; Benzodioxoles; Benzopyrans; Brain; Catechin; Cells, Cultured; Humans; Hydrazones; Lewy Bodies; Molecular Targeted Therapy; Neurofibrillary Tangles; Parkinson Disease; Protein Aggregates; Protein Aggregation, Pathological; Pyrazoles; alpha-Synuclein; tau Proteins
PubMed: 32732936
DOI: 10.1038/s41598-020-69744-y -
International Journal of Molecular... May 2023Some new Bis-pyrazoline hybrids with dual EGFR and BRAF inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer...
Some new Bis-pyrazoline hybrids with dual EGFR and BRAF inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds , , and demonstrated strong antiproliferative activity with GI values of 1.05 µM, 1.50 µM, and 1.20 µM, respectively. Hybrids showed dual inhibition of EGFR and BRAF. Compounds , , and inhibited EGFR-like erlotinib and exhibited promising anticancer activity. Compound is the most potent inhibitor of cancer cell proliferation and BRAF. Compounds and induced apoptosis by increasing caspase 3, 8, and Bax levels, and resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that compounds , , and have the potential to be dual EGFR/BRAF inhibitors. Additionally, in silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and adverse effects. DFT studies for the two most active compounds, and , were also carried out. The values of the HOMO and LUMO energies, as well as softness and hardness, were computationally investigated using the DFT method. These findings agreed well with those of the in vitro research and molecular docking study.
Topics: Humans; Apoptosis; Cell Line; Cell Proliferation; Cell Survival; Density Functional Theory; Drug Design; ErbB Receptors; Molecular Docking Simulation; Proto-Oncogene Proteins B-raf; Pyrazoles; Static Electricity; Structure-Activity Relationship; Antineoplastic Agents
PubMed: 37240450
DOI: 10.3390/ijms24109104