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Expert Opinion on Therapeutic Patents May 2024PIM Kinases (PIM-1, PIM-2, and PIM-3) have been reported to play crucial role in signaling cascades that govern cell survival, proliferation, and differentiation.... (Review)
Review
INTRODUCTION
PIM Kinases (PIM-1, PIM-2, and PIM-3) have been reported to play crucial role in signaling cascades that govern cell survival, proliferation, and differentiation. Over-expression of these kinases leads to hematological malignancies such as diffuse large B cell lymphomas (DLBCL), multiple myeloma, leukemia, lymphoma and prostate cancer etc. PIM kinases as biomarkers and potential therapeutic targets have shown promise toward precision cancer therapy. The selective PIM-1, PIM-2, and/or PIM-3 isoform inhibitors have shown significant results in patients with advanced stages of cancer including relapsed/refractory cancer.
AREAS COVERED
A comprehensive literature review of PIM Kinases (PIM-1, PIM-2, and PIM-3) in oncogenesis, the patented PIM kinase inhibitors (2016-Present), and their pharmacological and structural insights have been highlighted.
EXPERT OPINION
Recently, PIM kinases viz. PIM-1, PIM-2, and PIM-3 (members of the serine/threonine protein kinase family) as therapeutic targets have attracted considerable interest in oncology especially in hematological malignancies. The patented PIM kinase inhibitors comprised of heterocyclic (fused)ring structure(s) like indole, pyridine, pyrazine, pyrazole, pyridazine, piperazine, thiazole, oxadiazole, quinoline, triazolo-pyridine, pyrazolo-pyridine, imidazo-pyridazine, oxadiazole-thione, pyrazolo-pyrimidine, triazolo-pyridazine, imidazo-pyridazine, pyrazolo-quinazoline and pyrazolo-pyridine etc. showed promising results in cancer chemotherapy.
Topics: Humans; Patents as Topic; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-pim-1; Antineoplastic Agents; Animals; Neoplasms; Proto-Oncogene Proteins; Hematologic Neoplasms; Molecular Targeted Therapy; Drug Development; Drug Design; Protein Serine-Threonine Kinases
PubMed: 38842051
DOI: 10.1080/13543776.2024.2365411 -
Journal of Agricultural and Food... Jul 2024Liquor-pairing food is a common dietary combination. Baijiu and peanuts are unquestionably a classic pairing in China. But no one has explained why. Its alteration in...
Liquor-pairing food is a common dietary combination. Baijiu and peanuts are unquestionably a classic pairing in China. But no one has explained why. Its alteration in baijiu flavor was studied using multiple sensory evaluation, as well as nontargeted proton-transfer reaction mass spectrometry coupled with GC × GC-MS. Multiple statistical analyses were used to discover the changes in the retronasal aroma and its contribution to baijiu flavor. It showed that the consumption of peanuts enhances the burst intensity of ester aroma (0.814-1.00) and Jiao aroma (0.889-0.963) but decreases the aftertaste of baijiu ( < 0.05). Meanwhile, it increases the release intensity and advances the burst time of baijiu retronasal aroma ( < 0.05), suppressing its aftertaste through the retention effect of the food matrix, the changes in oral processing, and cross-modal interactions. Hydrophobicity, polarity, and chemical characteristics are key factors of the uneven impact of accompanying food to aroma compounds. Esters, especially ethyl caprylate (2103 ± 927 to 51.9 ± 4.05) is most impacted by peanuts and contributes most to baijiu flavor changes. Pyrazines from peanut enhance the Qu-aroma, grain aroma, and Chen aroma in baijiu flavor. Therefore, we revealed the chemical nature of baijiu-peanut combination and help to optimize baijiu consumption experience.
Topics: Humans; Arachis; Odorants; Taste; Adult; Gas Chromatography-Mass Spectrometry; Female; Male; Young Adult; China; Volatile Organic Compounds; Flavoring Agents; Alcoholic Beverages; Smell; Middle Aged
PubMed: 38841998
DOI: 10.1021/acs.jafc.4c00207 -
Food Chemistry: X Jun 2024The aim of this study deals with characterize the volatile profiles of gluten free flours and bakery products. An appropriate HS-SPME/GC-MS methods for the...
The aim of this study deals with characterize the volatile profiles of gluten free flours and bakery products. An appropriate HS-SPME/GC-MS methods for the quantification analyses was performed and corn starch solid as standards was used. 34 different samples were analysed, and 127 compounds distributed in 4 classes (alcohols, aldehydes and ketones, heterocyclic compounds, and terpenes), that make up the aroma of these gluten free, were identified. The developed method is characterized by detection limits of 0.0004 and 0.0047 mg/kg for camphor and pyrazine, respectively, and linearity of quantification standards were between 0.990 and 0.998 for a range of 3-50 mg/kg.
PubMed: 38840722
DOI: 10.1016/j.fochx.2024.101399 -
Journal of the College of Physicians... Jun 2024To evaluate the effect of favipiravir administered to diabetic and non-diabetic COVID-19 patients on the QT/QTc interval.
OBJECTIVE
To evaluate the effect of favipiravir administered to diabetic and non-diabetic COVID-19 patients on the QT/QTc interval.
STUDY DESIGN
Analytical study. Place and Duration of the Study: Republic of Turkey, Ministry of Health, State Hospital, Corlu, Tekirdag, Turkiye, from March to September 2021.
METHODOLOGY
Electrocardiogram (ECG) analysis was performed on all participants (n=180) divided into four groups. Group 1 included only healthy volunteers. Group 2 included only cases diagnosed with T2DM. Group 3 included only severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) cases. Group 4 included cases diagnosed with both SARS and T2DM. Favipiravir was administered only to the cases in Group 3 and Group 4. In the cases that were administered favipiravir, the QT/QTc interval was calculated and recorded at different time intervals on the first and fifth days of the therapy. The difference between groups was determined by Tukeye's test after ANOVA. Pearson's correlation test was used to determine whether there was a linear relationship between two numericals. The alpha significance value was determined to be <0.05 in all statistical analyses.
RESULTS
When all groups were compared, it was seen that both QT and QTc values increased in Groups 3 and 4, which were administered favipiravir (p <0.05). Favipiravir may cause an increased risk of ventricular and atrial arrhythmias.
CONCLUSION
Favipiravir may cause QT interval prolongation, particularly in SARS-Cov-2 patients diagnosed with T2DM.
KEY WORDS
COVID-19, Drug-induced long QT syndrome, Intra-infarct haemorrhage; Favipiravir, Type 2 diabetes mellitus.
Topics: Humans; Pyrazines; Amides; Male; Female; Electrocardiography; Middle Aged; Diabetes Mellitus, Type 2; Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Long QT Syndrome; SARS-CoV-2; Adult; Turkey; Aged
PubMed: 38840347
DOI: 10.29271/jcpsp.2024.06.659 -
Inorganic Chemistry Jun 2024The pyrazine-coordinated dinuclear and mononuclear ruthenium complexes were synthesized through the framework conversion reactions of the triply chlorido-bridged...
The pyrazine-coordinated dinuclear and mononuclear ruthenium complexes were synthesized through the framework conversion reactions of the triply chlorido-bridged diruthenium(II) complex [{Ru(bbpma)}(μ-Cl)] (bbpma; benzylbis(2-pyridylmethyl)amine, []) in the presence of pyrazine, which could function as the simple molecular multinucleation ligand of metal compounds. A reduction reaction of -[RuCl(bbpma)] with zinc in the presence of hydrochloric acid afforded [] in solution, and the following addition of pyrazine (1 equiv) in the solution led to the formation of a singly pyrazine (pz)-bridged diruthenium complex, [{Ru(μ-ClZnCl)(bbpma)}(μ-pz)] ([]). The stoichiometric two-electron oxidation of [] was successfully proceeded, and a Ru(III)-Ru(III) species, [{RuCl(bbpma)}(μ-pz)](PF) ([,](PF)), was isolated. The reaction of [] with excess amounts of pyrazine without hydrochloric acid afforded mononuclear Ru(III) and Ru(II) complexes containing one or two pyrazine, -[RuCl(pz)(bbpma)] ( = 2; []; = 1; []). The details of the electrochemical and spectroscopic properties of []-[] in organic and aqueous solutions were discussed.
PubMed: 38837355
DOI: 10.1021/acs.inorgchem.4c01001 -
Cellular and Molecular Biology... Jun 2024Skin photoaging is a skin degenerative disease that causes patients to develop malignant tumors. The existing clinical treatment of photoaging has limitations. This...
Skin photoaging is a skin degenerative disease that causes patients to develop malignant tumors. The existing clinical treatment of photoaging has limitations. This greatly reduces the recovery rate of photoaging patients. Studies have confirmed that Ligusticum wallichii Franch (LWF) monomer tetramethylpyrazine (TMP) alleviates various skin diseases. The combination of traditional Chinese medicine and Western medicine helps with this process. Our research aimed to explore the specific treatment mode and molecular mechanism of TMP in treating skin photoaging. CCK-8 assays were used to evaluate the activity and toxicity of HaCaT cells. β-galactosidase aging, Carbonyl compound and nitrosylated tyrosine assays were used to analyze the aging of HaCaT cells. ROS assays and ELISA were used to analyze the enrichment of ROS. The molecular docking experiment analyzed the binding of TMP and HIF-1α. qRT-PCR and Western blot were used to detect the activation of skin aging-related pathways. HE staining was used to analyze the thickness of the stratum corneum skin on the back skin of mice. 200μg/L LWF alleviates cellular photoaging and mouse skin photoaging by reducing ROS enrichment. Its monomer TMP plays an important role in this process. The combination of TMP and HIF-1α accelerates the degradation of ROS by activating the Nrf2/ARE signaling pathway. This process reduces the apoptosis of cells damaged by light. In addition, we also found that the combination of TMP and retinoic acid (RA) is more beneficial for the treatment of skin damage caused by light in mice. The combination therapy of TMP and RA alleviates skin oxidative stress response through overexpression of HIF-1α. This plan is beneficial for the treatment of skin photoaging.
Topics: Pyrazines; Skin Aging; Hypoxia-Inducible Factor 1, alpha Subunit; Animals; Humans; Reactive Oxygen Species; Mice; Signal Transduction; Vitamin A; Skin; HaCaT Cells; Molecular Docking Simulation
PubMed: 38836676
DOI: 10.14715/cmb/2024.70.6.14 -
Cellular and Molecular Biology... Jun 2024The prognosis of patients with multiple myeloma (MM) has significantly improved over the past ten years because of several innovative treatments, including the...
The prognosis of patients with multiple myeloma (MM) has significantly improved over the past ten years because of several innovative treatments, including the proteasome inhibitor Bortezomib and immunomodulatory drugs (IMiDs) like Thalidomide and Lenalidomide. The present study aimed to determine the effectiveness of Bortezomib-based regimens on survival state of MM patients. This retrospective study included 204 newly diagnosed MM patients who were registered at Nanakali Hospital for Blood Diseases and Cancer, Erbil- Iraq, between April 2008 and April 2022. The patients were split into two primary groups: those receiving treatment with Bortezomib and those not. Clinical and laboratory data, treatment type, responsiveness to induction therapy, and survival results were examined in the enrolled patients' medical records. The mean patient age was 60 years, males constituted 55.8% of the included patients. At the time of diagnosis, 98 individuals (48%) had stage 3 illness. Except for the LDH, which was noticeably higher in the non-Bortezomib group, the patients laboratory results did not substantially change between the Bortezomib and non-Bortezomib groups (p = 0.001). In patients treated with Bortezomib, the complete response (CR) rate following induction was substantially greater (35.2%) than in those treated without Bortezomib (9.1%). Compared to the non-Bortezomib group, the median survival time of the Bortezomib group was considerably greater (p < 0.001). Bortezomib has a significant role in inducing a CR before bone marrow (BM) transplantation, and it has a significant role in the survival outcome in MM.
Topics: Humans; Multiple Myeloma; Bortezomib; Male; Middle Aged; Female; Aged; Retrospective Studies; Treatment Outcome; Adult; Antineoplastic Combined Chemotherapy Protocols; Survival Analysis
PubMed: 38836665
DOI: 10.14715/cmb/2024.70.6.25 -
Journal of Chemical Theory and... Jun 2024In recent years, machine learning (ML) surrogate models have emerged as an indispensable tool to accelerate simulations of physical and chemical processes. However,...
In recent years, machine learning (ML) surrogate models have emerged as an indispensable tool to accelerate simulations of physical and chemical processes. However, there is still a lack of ML models that can accurately predict molecular vibrational spectra. Here, we present a highly efficient multitask ML surrogate model termed Vibrational Spectra Neural Network (VSpecNN), to accurately calculate infrared (IR) and Raman spectra based on dipole moments and polarizabilities obtained on-the-fly via ML-enhanced molecular dynamics simulations. The methodology is applied to pyrazine, a prototypical polyatomic chromophore. The VSpecNN-predicted energies are well within the chemical accuracy (1 kcal/mol), and the errors for VSpecNN-predicted forces are only half of those obtained from a popular high-performance ML model. Compared to the ab initio reference, the VSpecNN-predicted frequencies of IR and Raman spectra differ only by less than 5.87 cm, and the intensities of IR spectra and the depolarization ratios of Raman spectra are well reproduced. The VSpecNN model developed in this work highlights the importance of constructing highly accurate neural network potentials for predicting molecular vibrational spectra.
PubMed: 38825857
DOI: 10.1021/acs.jctc.4c00173 -
Hematological Oncology Jul 2024Daratumumab-based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real-world... (Observational Study)
Observational Study
Daratumumab-based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real-world data on daratumumab efficacy in upfront therapy in unselected patients are scanty. In the framework of a prospective observational study, we investigated the efficacy and safety of daratumumab in 88 newly diagnosed patients, including subjects with IIIb cardiac stage (26%) or myeloma defining events (29%). Daratumumab was administered with bortezomib in 50 (56%) patients, lenalidomide in 31 (35%), and monotherapy in 7 (8%). The rate of serious adverse events was low (16%). The overall hematologic response rate was 75% with 52 (59%) patients attaining at least a very good partial response (VGPR) at six months. Amongst patients evaluable for organ response, the rate of cardiac and renal responses at 6 months was 31% and 21%, respectively. Comparing stage IIIb patients with the remaining ones, the rate of profound hematologic response was not significantly different (≥VGPR 57% vs. 59%, p 0.955) likewise the rate of cardiac (33% vs. 30%, p 0.340) and renal (40% vs. 16%, p 0.908) responses. Daratumumab-based regimens demonstrated to be safe and effective in treatment-naïve AL amyloidosis even in advanced stage disease.
Topics: Humans; Male; Female; Antibodies, Monoclonal; Aged; Immunoglobulin Light-chain Amyloidosis; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Aged, 80 and over; Prospective Studies; Lenalidomide; Bortezomib; Adult; Treatment Outcome
PubMed: 38824453
DOI: 10.1002/hon.3289 -
Bioorganic Chemistry Aug 2024Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while...
Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, B3-2 exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that B3-2 induced FLT3-ITD degradation in a ubiquitin-proteasome-dependent manner. More importantly, B3-2 exhibited an oral bioavailability of 5.65%, and oral administration of B3-2 showed good antitumor activity in MV-4-11 xenograft models. Furthermore, B3-2 showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.
Topics: fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Antineoplastic Agents; Pyrazines; Cell Proliferation; Animals; Structure-Activity Relationship; Molecular Structure; Protein Kinase Inhibitors; Drug Screening Assays, Antitumor; Mice; Dose-Response Relationship, Drug; Drug Discovery; Thiophenes; Proteolysis; Aniline Compounds; Cell Line, Tumor; Neoplasms, Experimental
PubMed: 38820938
DOI: 10.1016/j.bioorg.2024.107477