Kinase inhibitor

Poor survival and lack of treatment response in glioblastoma (GBM) is attributed to the persistence of glioma stem cells (GSCs). To identify novel therapeutic approaches, we performed CRISPR/Cas9 knockout screens and discovered TGFβ activated kinase (TAK1) as a selective survival factor in a significant fraction of GSCs. Loss of TAK1 kinase activity results in RIPK1-dependent apoptosis via Caspase-8/FADD complex activation, dependent on autocrine TNFα ligand production and constitutive TNFR signaling...

BACKGROUND: No head-to-head clinical trials have compared the differences in adverse events (AEs) between nivolumab plus ipilimumab (NIVO-IPI) and nivolumab plus cabozantinib (NIVO-CABO) in the treatment of metastatic renal cell carcinoma (mRCC). AIM: We analysed the two largest real-world databases, the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the World Health Organization's VigiBase, to elucidate the differences in AEs between NIVO-IPI and NIVO-CABO...

The aim of this study was to investigate the expression and function of the transient receptor potential vanilloid 1 (TRPV1) in glioma. We found that the expression of TRPV1 mRNA and protein were upregulated in glioma compared with normal brain by qPCR and western blot analysis. In order to investigate the function of TRPV1 in glioma, short hairpin RNA (shRNA) and the inhibitor of TRPV1 were used. In vitro, the activation of TRPV1 induced cell apoptosis with decreased migration capability and inhibited proliferation, which was abolished upon TRPV1 pharmacological inhibition and silencing...

We explored the vasorelaxant effects of ipragliflozin, a sodium-glucose cotransporter-2 inhibitor, on rabbit femoral arterial rings. Ipragliflozin relaxed phenylephrine-induced pre-contracted rings in a dose-dependent manner. Pre-treatment with the ATP-sensitive K+ channel inhibitor glibenclamide (10 μM), the inwardly rectifying K+ channel inhibitor Ba2+ (50 μM), or the Ca2+ -sensitive K+ channel inhibitor paxilline (10 μM) did not influence the vasorelaxant effect. However, the voltage-dependent K+ (Kv) channel inhibitor 4-aminopyridine (3 mM) reduced the vasorelaxant effect...

The effect of endothelial cells' exposure to dibutyl phthalate (DBP) on monocyte adhesion is largely unknown. We evaluated monocyte adhesion to DBP-exposed endothelial cells by combining three approaches: short-term exposure (24 h) of EA.hy926 cells to 10-6 , 10-5 , and 10-4 M DBP, long-term exposure (12 weeks) of EA.hy926 cells to 10-9 , 10-8 , and 10-7 M DBP, and exposure of rats (28 and 90 days) to 100, 500, and 5000 mg DBP/kg food. Monocyte adhesion to human EA.hy926 and rat aortic endothelial cells, expression of selected cellular adhesion molecules and chemokines, and the involvement of extracellular signal-regulated kinase 1/2 (ERK1/2) were analyzed...

OBJECTIVE: To explore pre-treatment imaging findings of neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasm, an emerging group of molecularly defined soft tissue tumors and summarize the clinical course, including TRK inhibitor therapy response. MATERIALS AND METHODS: This retrospective study included 8 women and 4 men with NTRK-rearranged spindle cell neoplasm (median age, 35.5 years, range, 0-66). Available pre-treatment MRI, CT, PET, and US imaging were reviewed...

BACKGROUND: Peritoneal metastases (PM) have been reported in approximately 1% of patients with metastatic Renal Cell Carcinoma (mRCC). Outcome data are limited due to the rarity of this metastatic site. Therefore, the aim of our study is to describe renal cell carcinoma (RCC) patients with PM treated as per clinical practice. MATERIALS AND METHODS: Baseline characteristics and outcome data of patients with PM from RCC were retrospectively collected from 18 Italian oncological referral centers adhering to the Meet-Uro group, from January 2016 to January 2023...

Recently, we have developed novel Pim-1 kinase inhibitors starting from a dihydrobenzofuran core structure using a computational approach. Here, we report the design and synthesis of stilbene-based Pim-1 kinase inhibitors obtained by formal elimination of the dihydrofuran ring. These inhibitors of the first design cycle, which were obtained as inseparable cis/trans mixtures, showed affinities in the low single-digit micromolar range. To be able to further optimize these compounds in a structure-based fashion, we determined the X-ray structures of the protein-ligand-complexes...

The tight control of proliferating keratinocytes is vital to the successful function of the skin. Differentiation of dividing cells is necessary to form a skin barrier. The same dividing cells are necessary to heal wounds and when malignant form tumors. RIPK4, a serine-threonine kinase, plays critical roles in these processes. Its loss of function was associated with pathological keratinocyte proliferation and development of squamous cell carcinoma (SCC) in humans and mice. The current study extends previous findings in the importance of RIPK4 in keratinocyte proliferation...

PURPOSE: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) indicated for the treatment of EGFR mutated (EGFRm)-driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line treated patients with EGFRm advanced NSCLC. Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression. EXPERIMENTAL DESIGN: ctDNA profiling analysis on-progression plasma samples from patients treated with osimertinib in both first (Phase 3, FLAURA trial) and second-line trials (Phase 3, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations...

INTRODUCTION: The emergence of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC) has revolutionized targeted therapy. This dynamic landscape, featuring novel ALK inhibitors and combination therapies, necessitates a profound understanding of resistance mechanisms for effective treatment strategies. Recognizing two primary categories - on-target and off-target resistance - underscores the need for comprehensive assessment. AREAS COVERED: This review delves into the intricacies of resistance to ALK inhibitors, exploring complexities in identification and management...

An efficient protocol for the synthesis of β-trifluoroethoxydimethyl selenides was achieved under mild reaction conditions, and 39 compounds were prepared. All compounds were evaluated for their abilities to inhibit RANKL-induced osteoclastogenesis, compound 4aa exhibited the most potent activity. Further investigations revealed that 4aa could inhibit F-actin ring generation, bone resorption, and osteoclast-specific gene expression in vitro . Western blot analyses demonstrated that compound 4aa abrogated the RANKL-induced mitogen-activated protein kinase and NF-kB-signaling pathways...

Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It has higher aggressiveness and metastasis than other subtypes, with limited effective therapeutic strategies, leading to a poor prognosis. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway is prevalently over-activated in human cancers and contributes to breast cancer (BC) growth, survival, proliferation, and angiogenesis, which could be an interesting therapeutic target...

Among the most prevalent forms of cancer are breast, lung, colon-rectum, and prostate cancers, and breast cancer is a major global health challenge, contributing to 2.26 million cases with approximately 685,000 deaths worldwide in 2020 alone, typically beginning in the milk ducts or lobules that produce and transport milk during lactation and it is becoming challenging to treat as the tissues are developing resistance, which makes urgent calls for new multitargeted drugs. The multitargeted drug design provides a better solution, simultaneously targeting multiple pathways, even when the drug resists one, it remains effective for others...

The natural product (-)-TAN-2483B is a fungal secondary metabolite which displays promising anti-cancer and immunomodulatory activity. Our previous syntheses of (-)-TAN-2483B and sidechain analogues uncovered inhibitory activity against Bruton's tyrosine kinase (Btk), an established drug target for various leukaemia and immunological diseases. A structure-based computational study using ensemble docking and molecular dynamics was performed to determine plausible binding modes for (-)-TAN-2483B and analogues in the Btk binding site...

Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of the JAK2 gene, including JAK2V617F or several others in exon 12. A 38-year-old female had a stroke at age 32 and found to have elevated hemoglobin, normal leukocytes, normal platelets, and tested negative for JAK2V617F and exon 12 mutations. Next generation sequencing revealed a novel mutation: JAK2R715T in the pseudokinase domain (JH2) at 47.5%. Its presence in her nail DNA confirmed a germline origin. Her mother and her son similarly had erythrocytosis and a JAK2R715T mutation...

A natural aging mouse model can exhibit physiological characteristics that closely resemble those of human aging. Through long-term observation, it reflects the occurrence and development of the aging process more accurately. Although numerous beneficial effects of royal jelly (RJ) have been extensively demonstrated in multiple experimental models, the effects of RJ on naturally aging mice have not yet been investigated. In this study, middle-aged male C57BL/6J mice were given RJ for 9 consecutive months to investigate its impact on the intestinal barrier function, gut microbiota, short-chain fatty acids (SCFAs) content and possible mechanisms...

INTRODUCTION: Epilepsy is a chronic neurological condition characterized by a persistent propensity for seizure generation. About one-third of patients do not achieve seizure control with the first-line treatment options, which include > 20 antiseizure medications. It is therefore imperative that new medications with novel targets and mechanisms of action are developed. AREAS COVERED: Clinical studies and preclinical research increasingly implicate Non-receptor tyrosine kinases (nRTKs) in the pathogenesis of epilepsy...

BACKGROUND: The proto-oncogene ROS1 encodes an intrinsic type I membrane protein of the tyrosine kinase/insulin receptor family. ROS1 facilitates the progression of various malignancies via self-mutations or rearrangements. Studies on ROS1-directed tyrosine kinase inhibitors have been conducted, and some have been approved by the FDA for clinical use. However, the adverse effects and mechanisms of resistance associated with ROS1 inhibitors remain unknown. In addition, next-generation ROS1 inhibitors, which have the advantage of treating central nervous system metastases and alleviating endogenous drug resistance, are still in the clinical trial stage...

Infantile fibrosarcomas (IFS) and congenital mesoblastic nephroma (CMN) are rare myofibroblastic tumors of infancy and early childhood commonly harboring the ETV6::NTRK3 gene fusion. IFS/CMN are considered as tumors with an 'intermediate prognosis' as they are locally aggressive, but rarely metastasize, and generally have a favorable outcome. A fraction of IFS/CMN-related neoplasms are negative for the ETV6::NTRK3 gene rearrangement and are characterized by other chimeric proteins promoting MAPK signaling upregulation...