The Lysosomal sequestration of weak-base anticancer drugs is one putative mechanism for resistance to chemotherapy but it has never been directly proven. We addressed the question of whether the lysosomal sequestration of tyrosine kinase inhibitors (TKIs) itself contributes to the drug resistance in vitro. Our analysis indicates that lysosomal sequestration of an anticancer drug can significantly reduce the concentration at target sites, only when it simultaneously decreases its extracellular concentration due to equilibrium, since uncharged forms of weak-base drugs freely diffuse across cellular membranes. Even though the studied TKIs, including imatinib, nilotinib, and dasatinib, were extensively accumulated in the lysosomes of cancer cells, their sequestration was insufficient to substantially reduce the extracellular drug concentration. Lysosomal accumulation of TKIs also failed to affect the Bcr-Abl signaling. Cell pre-treatment with sunitinib significantly enhanced the lysosomal accumulation of the TKIs used; however, without apparent lysosomal biogenesis. Importantly, even increased lysosomal sequestration of TKIs neither decreased their extracellular concentrations nor affected the sensitivity of Bcr-Abl to TKIs. In conclusion, our results clearly show that the lysosomal sequestration of TKIs failed to change their concentrations at target sites, and thus, can hardly contribute to drug resistance in vitro.

• Klíčová slova
• drug resistance, extracellular space, extralysosomal space, lysosomal sequestration, target sites, tyrosine kinase inhibitors,
• MeSH
• buňky K562 MeSH
• chemorezistence * MeSH
• extracelulární prostor účinky léků   metabolismus   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• lyzozomy účinky léků   metabolismus   MeSH
• sunitinib farmakologie   MeSH
• tyrosinkinasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• sunitinib MeSH
• tyrosinkinasy MeSH

Bruton's tyrosine kinase (BTK) is a promising molecular target for several human B-cell-related autoimmune disorders, inflammation, and haematological malignancies. The pathogenic alterations in various cancer tissues depend on mutant BTK for cell proliferation and survival, and BTK is also overexpressed in a range of hematopoietic cells. Due to this, BTK is emerging as a potential drug target to treat various human diseases, and several reversible and irreversible inhibitors have been developed and are being developed. As a result, BTK inhibition, clinically validated as an anticancer treatment, is finding great interest in B-cell malignancies and solid tumours. This study focuses on the design and synthesis of new oxindole sulfonamide derivatives as promising inhibitors of BTK with negligible off-target effects. The most cytotoxic compounds with greater basicity were PID-4 (2.29±0.52 μM), PID-6 (9.37±2.47 μM), and PID-19 (2.64±0.88 μM). These compounds caused a selective inhibition of Burkitt's lymphoma RAMOS cells without significant cytotoxicity in non-BTK cancerous and non-cancerous cell lines. Further, PID-4 showed promising activity in inhibiting BTK and downstream signalling cascades. As a potent inhibitor of Burkitt's lymphoma cells, PID-4 is a promising lead for developing novel chemotherapeutics.

• Klíčová slova
• Antiproliferation, B-cell malignancies, Bruton's tyrosine kinase, Cytotoxicity, Knoevenagel condensation, Oxindole sulfonamide,
• MeSH
• Burkittův lymfom * farmakoterapie   MeSH
• inhibitory proteinkinas MeSH
• inhibitory tyrosinkinasy * MeSH
• lidé MeSH
• proteinkinasa BTK MeSH
• sulfonamidy farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• inhibitory tyrosinkinasy * MeSH
• proteinkinasa BTK MeSH
• sulfonamidy MeSH

Cancer is one of the leading causes of death with a mortality rate of 12%. Although significant progress has been achieved in cancer research, the effective treatment of cancer remains the greatest global challenge in medicine. Dysregulation of tyrosine kinases (TK) is one of the characteristics of several types of cancers. Thus, drugs that target and inhibit these enzymes, known as TK inhibitors (TKIs), are considered vital chemotherapeutics to combat various types of cancer. The oral bioavailability of available TKIs and their targeted therapy are their potential benefits. Based on these characteristics, most TKIs are included in first/second-line therapy for the treatment of different cancers. This review aims to shed light on orally-active TKIs (natural and synthetic molecules) and their promising implication in the therapy of numerous types of tumors along with their mechanisms of action. Further, recent progress in the development of synthetic and isolation of natural TKIs is reviewed. A significant growth in research regarding the development of new-generation TKIs is made with time (23 FDA-approved TKIs from 2018) due to their better therapeutic response. Oral bioavailability should be considered as an important parameter while developing of new-generation TKIs; however, drug delivery systems can also be used to address issue of poor bioavailability to a certain extent. Moreover, clinical trials should be designed in consideration of the development of resistance and tumor heterogeneity.

• Klíčová slova
• Drug discovery, Enzyme-catalyzed reaction, Mechanistic enzymology, Natural compounds, Tyrosine kinase inhibitors,
• MeSH
• chemorezistence účinky léků   MeSH
• cílená molekulární terapie MeSH
• inhibitory proteinkinas aplikace a dávkování   farmakologie   MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• mutace účinky léků   MeSH
• nádory farmakoterapie   MeSH
• protinádorové látky farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• protinádorové látky MeSH
• tyrosinkinasy MeSH

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show potent efficacy in several ALK-driven tumors, but the development of resistance limits their long-term clinical impact. Although resistance mechanisms have been studied extensively in ALK-driven non-small cell lung cancer, they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase γ (PI3K-γ) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kγ expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kγ, and PI3Kδ were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kγ isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kγ/δ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kγ or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.

• MeSH
• anaplastická lymfomová kináza MeSH
• anaplastický velkobuněčný lymfom * farmakoterapie   genetika   patologie   MeSH
• endoteliální buňky metabolismus   MeSH
• fosfatidylinositol-3-kinasy MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• inhibitory tyrosinkinasy MeSH
• krizotinib farmakologie   terapeutické užití   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí MeSH
• nádory plic * farmakoterapie   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   MeSH
• receptory CCR7 genetika   MeSH
• tyrosinkinasové receptory metabolismus   MeSH
• tyrosinkinasy MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• anaplastická lymfomová kináza MeSH
• CCR7 protein, human MeSH Prohlížeč
• fosfatidylinositol-3-kinasy MeSH
• inhibitory proteinkinas MeSH
• inhibitory tyrosinkinasy MeSH
• krizotinib MeSH
• receptory CCR7 MeSH
• tyrosinkinasové receptory MeSH
• tyrosinkinasy MeSH

Recent progress in nanomedicine and targeted therapy brings new breeze into the field of therapeutic applications of tyrosine kinase inhibitors (TKIs). These drugs are known for many side effects due to non-targeted mechanism of action that negatively impact quality of patients' lives or that are responsible for failure of the drugs in clinical trials. Some nanocarrier properties provide improvement of drug efficacy, reduce the incidence of adverse events, enhance drug bioavailability, helps to overcome the blood-brain barrier, increase drug stability or allow for specific delivery of TKIs to the diseased cells. Moreover, nanotechnology can bring new perspectives into combination therapy, which can be highly efficient in connection with TKIs. Lastly, nanotechnology in combination with TKIs can be utilized in the field of theranostics, i.e. for simultaneous therapeutic and diagnostic purposes. The review provides a comprehensive overview of advantages and future prospects of conjunction of nanotransporters with TKIs as a highly promising approach to anticancer therapy.

• Klíčová slova
• Bioavailability, Drug delivery, Nanotechnology, Targeted therapy,
• MeSH
• inhibitory proteinkinas aplikace a dávkování   chemie   farmakologie   MeSH
• lékové transportní systémy * MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• nanomedicína * MeSH
• nanostruktury aplikace a dávkování   chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• inhibitory proteinkinas MeSH

Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR) signaling pathway, crucial for B-cell survival and proliferation. The first-in-class irreversible BTK inhibitor, ibrutinib, was approved for various B-cell malignancies but has limitations due to off-target effects. Second-generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti-CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis-targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK-targeted therapies provide hope for improved outcomes in patients with B-cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens.

• Klíčová slova
• BTK, inhibitor, resistance, zanubrutinib,
• MeSH
• B-buněčný lymfom farmakoterapie   metabolismus   patologie   MeSH
• chemorezistence * MeSH
• inhibitory proteinkinas * terapeutické užití   farmakologie   MeSH
• inhibitory tyrosinkinasy MeSH
• lidé MeSH
• piperidiny * terapeutické užití   farmakologie   MeSH
• proteinkinasa BTK * antagonisté a inhibitory   MeSH
• pyrazoly * terapeutické užití   farmakologie   MeSH
• pyrimidiny * terapeutické užití   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• BTK protein, human MeSH Prohlížeč
• inhibitory proteinkinas * MeSH
• inhibitory tyrosinkinasy MeSH
• piperidiny * MeSH
• proteinkinasa BTK * MeSH
• pyrazoly * MeSH
• pyrimidiny * MeSH
• zanubrutinib MeSH Prohlížeč

Herein, we report an efficient synthetic approach towards trisubstituted imidazo [4,5-c]pyridines designed as inhibitors of Bruton's tyrosine kinase (BTK). Two alternative synthetic routes for the simple preparation of desired compounds with variable substitutions at the N1, C4, C6 positions were introduced with readily available building blocks. Further, the developed synthetic approach was feasible for isomeric compounds bearing imidazo [4,5-b]pyridine scaffolds. In contrast to expectations based on previous studies, the imidazo [4,5-c]pyridine inhibitor exhibited a significantly higher activity against BTK compared to its imidazo [4,5-b]pyridine isomer. An inherent SAR study in the series of imidazo [4,5-c]pyridine compounds revealed a remarkably high tolerance of C6 substitutions for both hydrophobic and hydrophilic substituents. Preliminary cellular experiments indicated selective BTK targeting in Burkitt lymphoma and mantle cell lymphoma cell lines. The inhibitors could thus serve as starting points for further development, eventually leading to BTK inhibitors that could be used after ibrutinib failure.

• Klíčová slova
• Bruton’s tyrosine kinase, Inhibitor, Protein kinase, imidazo[4,5-c]pyridine,
• MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nehodgkinský lymfom farmakoterapie   MeSH
• proteinkinasa BTK antagonisté a inhibitory   MeSH
• pyridiny farmakologie   terapeutické užití   MeSH
• signální transdukce MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• proteinkinasa BTK MeSH
• pyridiny MeSH

Mast cells and basophils are major effector cells in the immunoglobulin E (IgE)-dependent allergic reactions as well as in the innate immunity. They are distributed throughout the body and, upon allergen exposure, are stimulated via the high affinity IgE receptor (FcepsilonRI) to release several pro-inflammatory mediators such as leukotrienes, immunoregulatory cytokines and histamine. FcepsilonRI-mediated signaling is initiated by tyrosine phosphorylation of FcepsilonRI subunits by Src family kinase Lyn, which is followed by an activation of Syk/Zap family kinase Syk. The activated kinases then in turn phosphorylate and activate other enzymes [phospholipase Cgamma (PLCgamma) isoforms, phosphatidylinositol-3 kinase (PI3K) isoforms, protein kinase C (PKC) isoforms, Bruton's tyrosine kinase (Btk) and others], adaptors [linker for activation of T cells (LAT), Cbl, Grb2 and others] and GTP exchange factors/GTPases (Vav, Ras, Rho, and others), and subsequently induce the mobilization of stored and extracellular Ca(2+). These and other biochemical events lead within seconds and minutes to the secretory response and later to the production of chemokines. This review is focused on the use of tyrosine kinase inhibitors specific for Src family kinases (PP1/PP2, SU6656 and CT5269), Syk kinase (piceatannol, ER-27319 and BAY 61-3606) and Btk (terreic acid and LFM-A13) for a modulation of FcepsilonRI-mediated signaling in mast cells. Potential use of the inhibitors in the treatment of inflammatory and allergy diseases as well as future directions in the development of highly specific tyrosine kinases inhibitors of new generations and their use in an intended modulation of mast cell signaling are discussed.

• MeSH
• alergie farmakoterapie   imunologie   MeSH
• inhibitory enzymů metabolismus   terapeutické užití   MeSH
• lidé MeSH
• receptory IgE metabolismus   fyziologie   MeSH
• signální transdukce účinky léků   imunologie   MeSH
• tyrosinkinasy antagonisté a inhibitory   metabolismus   MeSH
• zánět farmakoterapie   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• inhibitory enzymů MeSH
• receptory IgE MeSH
• tyrosinkinasy MeSH

BACKGROUND: Therapeutic drug monitoring is recommended for the optimal management of patients with several malignant diseases. The aim of this study was to develop and validate an isotope dilution direct injection mass spectrometry method for the high throughput determination of tyrosine kinase inhibitors in plasma from leukemic and cancer patients. METHODS: The plasma for analysis was deproteinated by methanol and the centrifuged supernatant was directly injected to mass spectrometer without separation step. Multiple reaction monitoring modes on a hybrid triple quadrupole - linear ion trap mass spectrometer (5500 QTRAP) were used for the detection and quantification of imatinib, nilotinib, lapatinib, and dasatinib. RESULTS: We developed a fast method with analysis time of 55 s and 19s in multiple injection setting. The method was successfully validated and applied to the patient plasma samples. In order to overcome insufficient sensitivity of dasatinib, multiple reaction monitoring cube mode in linear ion trap (MRM(3)) was successfully applied. The limits of quantification were in the range 1.0-5.5 ng/ml. Imprecisions were lower than 6.9% and the accuracy of the quality control samples ranged between 99.0 and 107.9%. CONCLUSIONS: Isotope dilution direct injection mass spectrometry method allows high-throughput therapeutic drug monitoring of tyrosine kinase inhibitors in plasma. The method offers low-cost analyses as a result of its speed and the exclusion of separation step and can be advantageously used in routine clinical practice. The method can be applied on various drugs and biochemical markers with the use of triple quadrupole instruments.

• MeSH
• biochemická analýza krve ekonomika   metody   MeSH
• časové faktory MeSH
• hmotnostní spektrometrie ekonomika   metody   MeSH
• inhibitory proteinkinas krev   MeSH
• injekce * MeSH
• izotopy MeSH
• lidé MeSH
• metody pro přípravu analytických vzorků MeSH
• reprodukovatelnost výsledků MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• izotopy MeSH
• tyrosinkinasy MeSH

BACKGROUND AND OBJECTIVE: Papillary renal cell carcinoma (pRCC) is the most frequent histological subtype of non-clear cell RCC (nccRCC). Owing to the heterogeneity of nccRCC, patients are often excluded from large phase 3 trials focused on clear cell RCC, so treatment options for nccRCC remain limited. Our aim was to investigate the efficacy of first-line treatment with tyrosine kinase inhibitors (TKIs) or immuno-oncology (IO)-based combinations in patients with pRCC. METHODS: We performed a multicenter retrospective analysis of real-world data collected for patients with advanced pRCC treated in 40 centers in 12 countries as part of the ARON-1 project (NCT05287464). The primary endpoints were overall survival (OS), progression-free survival (PFS), the overall response rate (ORR), and time to second progression (PFS2). OS, PFS, and PFS2 were estimated using the Kaplan-Meier method and results were compared between the treatment groups using a log-rank test. Univariate and multivariable analyses were carried out using Cox proportional-hazard models. KEY FINDINGS AND LIMITATIONS: We included 200 patients with metastatic pRCC, of whom 73 were treated with IO-based combinations and 127 with TKIs. Median OS was 22.5 mo in the TKI group 28.8 mo in the IO group (p = 0.081). Median PFS was 6.4 mo in the TKI group and 17.4 mo in the IO group (p < 0.001). The ORR was higher in the IO group than in the TKI group (41% vs 27%; p = 0.037). CONCLUSIONS AND CLINICAL IMPLICATIONS: Our results show that IO-based combinations have superior efficacy outcomes to TKIs for first-line treatment of metastatic pRCC. PATIENT SUMMARY: The ARON-1 project collects clinical data for patients with kidney cancer treated in multiple centers worldwide to assess outcomes in the real-world setting. We analyzed data for patients with metastatic kidney cancer of a specific subtype to evaluate the efficacy of different first-line treatments. Patients treated with immune-based combinations had better outcomes than patients treated with tyrosine kinase inhibitors.

• Klíčová slova
• ARON-1, Immuno-oncology combinations, Immunotherapy, Papillary renal cell carcinoma, Survival, Tyrosine kinase inhibitors,
• MeSH
• dospělí MeSH
• inhibitory proteinkinas * terapeutické užití   MeSH
• inhibitory tyrosinkinasy MeSH
• karcinom z renálních buněk * farmakoterapie   mortalita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory ledvin * farmakoterapie   mortalita   patologie   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• inhibitory proteinkinas * MeSH
• inhibitory tyrosinkinasy MeSH