MAPK-Activated Protein Kinases: Servant or Partner?

Mitogen-activated protein kinase (MAPK)-activated protein kinases (MAPKAPKs) are defined by their exclusive activation by MAPKs. They can be activated by classical and atypical MAPKs that have been stimulated by mitogens and various stresses. Genetic deletions of MAPKAPKs and availability of highly specific small-molecule inhibitors have continuously increased our functional understanding of these kinases. MAPKAPKs cooperate in the regulation of gene expression at the level of transcription; RNA processing, export, and stability; and protein synthesis. The diversity of stimuli for MAPK activation, the crosstalk between the different MAPKs and MAPKAPKs, and the specific substrate pattern of MAPKAPKs orchestrate immediate-early and inflammatory responses in space and time and ensure proper control of cell growth, differentiation, and cell behavior. Hence, MAPKAPKs are promising targets for cancer therapy and treatments for conditions of acute and chronic inflammation, such as cytokine storms and rheumatoid arthritis.

EGFR/IGF1R Signaling Modulates Relaxation in Hypertrophic Cardiomyopathy.

BACKGROUND: Diastolic dysfunction is central to diseases such as heart failure with preserved ejection fraction and hypertrophic cardiomyopathy (HCM). However, therapies that improve cardiac relaxation are scarce, partly due to a limited understanding of modulators of cardiomyocyte relaxation. We hypothesized that cardiac relaxation is regulated by multiple unidentified proteins and that dysregulation of kinases contributes to impaired relaxation in patients with HCM. METHODS: We optimized and increased the throughput of unloaded shortening measurements and screened a kinase inhibitor library in isolated adult cardiomyocytes from wild-type mice. One hundred fifty-seven kinase inhibitors were screened. To assess which kinases are dysregulated in patients with HCM and could contribute to impaired relaxation, we performed a tyrosine and global phosphoproteomics screen and integrative inferred kinase activity analysis using HCM patient myocardium. Identified hits from these 2 data sets were validated in cardiomyocytes from a homozygous MYBPC3c.2373insG HCM mouse model. RESULTS: Screening of 157 kinase inhibitors in wild-type (N=33) cardiomyocytes (n=24 563) resulted in the identification of 17 positive inotropes and 21 positive lusitropes, almost all of them novel. The positive lusitropes formed 3 clusters: cell cycle, EGFR (epidermal growth factor receptor)/IGF1R (insulin-like growth factor 1 receptor), and a small Akt (α-serine/threonine protein kinase) signaling cluster. By performing phosphoproteomic profiling of HCM patient myocardium (N=24 HCM and N=8 donors), we demonstrated increased activation of 6 of 8 proteins from the EGFR/IGFR1 cluster in HCM. We validated compounds from this cluster in mouse HCM (N=12) cardiomyocytes (n=2023). Three compounds from this cluster were able to improve relaxation in HCM cardiomyocytes. CONCLUSIONS: We showed the feasibility of screening for functional modulators of cardiomyocyte relaxation and contraction, parameters that we observed to be modulated by kinases involved in EGFR/IGF1R, Akt, cell cycle signaling, and FoxO (forkhead box class O) signaling, respectively. Integrating the screening data with phosphoproteomics analysis in HCM patient tissue indicated that inhibition of EGFR/IGF1R signaling is a promising target for treating impaired relaxation in HCM.

MASLD-Related HCC: A Comprehensive Review of the Trends, Pathophysiology, Tumor Microenvironment, Surveillance, and Treatment Options.

Hepatocellular carcinoma (HCC) represents a significant burden on global healthcare systems due to its considerable incidence and mortality rates. Recent trends indicate an increase in the worldwide incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) and a shift in the etiology of HCC, with MASLD replacing the hepatitis B virus as the primary contributor to new cases of HCC. MASLD-related HCC exhibits distinct characteristics compared to viral HCC, including unique immune cell profiles resulting in an overall more immunosuppressive or exhausted tumor microenvironment. Furthermore, MASLD-related HCC is frequently identified in older age groups and among individuals with cardiometabolic comorbidities. Additionally, a greater percentage of MASLD-related HCC cases occur in noncirrhotic patients compared to those with viral etiologies, hindering early detection. However, the current clinical practice guidelines lack specific recommendations for the screening of HCC in MASLD patients. The evolving landscape of HCC management offers a spectrum of therapeutic options, ranging from surgical interventions and locoregional therapies to systemic treatments, for patients across various stages of the disease. Despite ongoing debates, the current evidence does not support differences in optimal treatment modalities based on etiology. In this study, we aimed to provide a comprehensive overview of the current literature on the trends, characteristics, clinical implications, and treatment modalities for MASLD-related HCC.

Phase I trial of apatinib and paclitaxel+oxaliplatin+5-FU/levoleucovorin for treatment-naïve advanced gastric cancer.

Chinese guidelines recommend POF (paclitaxel, oxaliplatin, and 5-FU/levoleucovorin) as first-line treatment for advanced gastric cancer (AGC). Apatinib can augment the antitumor effect of paclitaxel, oxaliplatin, or fluorouracil in preclinical studies of AGC. A phase I clinical trial was conducted to evaluate the anticancer activity and maximum tolerated dose (MTD) of apatinib plus POF in treatment-naïve patients with AGC and to establish a recommended phase II dose. Participants received escalating doses of daily oral apatinib (250, 375, 500, 625, 750, and 850 mg) plus POF every 2 weeks using a conventional "3 + 3" study design. Among 21 treated patients, one experienced a dose-limiting toxicity (grade 3 skin ulceration at 850 mg). No MTD was reached. Apatinib 750 mg plus POF was recommended for phase II study. The most common grade 3-4 adverse events (AEs) were neutropenia (33.3%), mucositis (14.3%), and hand-foot syndrome (14.3%). Median progression-free and overall survival were 10.4 months (95% CI: 6.3, 14.6) and 18.4 months (95% CI: 9.8, 28.2), respectively. Apatinib up to 850 mg coadministered with POF was well tolerated with manageable AEs. The safety and anticancer activity of this regimen warrants its further investigation as first-line treatment for AGC in a larger study.

Lenvatinib plus pembrolizumab for patients with previously treated, advanced, triple-negative breast cancer: Results from the triple-negative breast cancer cohort of the phase 2 LEAP-005 Study.

BACKGROUND: Novel treatments are needed for patients with advanced, triple-negative breast cancer (TNBC) that progresses or recurs after first-line treatment with chemotherapy. The authors report results from the TNBC cohort of the multicohort, open-label, single-arm, phase 2 LEAP-005 study of lenvatinib plus pembrolizumab in patients with advanced solid tumors (ClinicalTrials.gov identifier NCT03797326). METHODS: Eligible patients had metastatic or unresectable TNBC with disease progression after one or two lines of therapy. Patients received lenvatinib (20 mg daily) plus pembrolizumab (200 mg every 3 weeks; up to 35 cycles). The primary end points were the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1, and safety (adverse events graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0). Duration of response, progression-free survival, and overall survival were secondary end points. RESULTS: Thirty-one patients were enrolled. The objective response rate by investigator assessment was 23% (95% confidence interval [CI], 10%-41%). Overall, the objective response rate by blinded independent central review (BICR) was 32% (95% CI, 17%-51%); and, in patients who had programmed cell death ligand 1 combined positive scores ≥10 (n = 8) and <10 (n = 22), the objective response rate was 50% (95% CI, 16%-84%) and 27% (95% CI, 11%-50%), respectively. The median duration of response by BICR was 12.1 months (range, from 3.0+ to 37.9+ months). The median progression-free survival by BICR was 5.1 months (95% CI, 1.9-11.8 months) and the median overall survival was 11.4 months (95% CI, 4.1-21.7 months). Treatment-related adverse events occurred in 94% of patients (grade 3, 52%; grade 4, 0%). One patient died due to a treatment-related adverse event of subarachnoid hemorrhage. CONCLUSIONS: The combination of lenvatinib plus pembrolizumab demonstrated antitumor activity with a manageable safety profile in patients with previously treated, advanced TNBC.

Phenotypic screening in Organ-on-a-Chip systems: a 1537 kinase inhibitor library screen on a 3D angiogenesis assay.

Modern drug development increasingly requires comprehensive models that can be utilized in the earliest stages of compound and target discovery. Here we report a phenotypic screening exercise in a high-throughput Organ-on-a-Chip setup. We assessed the inhibitory effect of 1537 protein kinase inhibitors in an angiogenesis assay. Over 4000 micro-vessels were grown under perfusion flow in microfluidic chips, exposed to a cocktail of pro-angiogenic factors and subsequently exposed to the respective kinase inhibitors. Efficacy of compounds was evaluated by reduced angiogenic sprouting, whereas reduced integrity of the main micro-vessel was taken as a measure for toxicity. The screen yielded 53 hits with high anti-angiogenicity and low toxicity, of which 44 were previously unassociated with angiogenic pathways. This study demonstrates that Organ-on-a-Chip models can be screened in high numbers to identify novel compounds and targets. This will ultimately reduce bias in early-stage drug development and increases probability to identify first in class compounds and targets for today's intractable diseases.

Lenvatinib plus pembrolizumab for patients with previously treated advanced ovarian cancer: Results from the phase 2 multicohort LEAP-005 study.

OBJECTIVES: The phase 2, multicohort, open-label LEAP-005 study evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors. We report outcomes from the ovarian cancer cohort. METHODS: Eligible patients had metastatic/unresectable ovarian cancer and had received 3 previous lines of therapy. Patients received lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks. Treatment continued until progression, unacceptable toxicity, or (for pembrolizumab) completion of 35 cycles. Primary endpoints were objective response rate (ORR) per RECIST version 1.1 and safety. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-one patients were enrolled. 39% had high grade serous ovarian cancer, 23% were platinum-sensitive, 55% were platinum-resistant, 23% were platinum-refractory, and 84% had tumors that had a PD-L1 combined positive (CPS) score ≥1. ORR (95% CI) was 26% (12%-45%) by investigator assessment and 35% (19%-55%) by blinded independent central review (BICR). Per BICR, median DOR was 9.2 (1.5+ to 37.8+) months. ORRs (95% CI) by BICR were 35% (9/26 patients; 17%-56%) for PD-L1 CPS ≥ 1 disease and 50% (2/4 patients; 7%-93%) for PD-L1 CPS < 1 disease. Median (95% CI) PFS by BICR and OS were 6.2 (4.0-8.5) months and 21.3 (11.7-32.3) months, respectively. Treatment-related AEs occurred in 94% of patients (grade 3-4, 77%). One patient died from treatment-related hypovolemic shock. CONCLUSIONS: Lenvatinib plus pembrolizumab demonstrated antitumor activity as fourth line therapy in patients with advanced ovarian cancer, and no unanticipated safety signals were identified. Responses were observed regardless of PD-L1 status.

Rivoceranib, a VEGFR-2 inhibitor, monotherapy in previously treated patients with advanced or metastatic gastric or gastroesophageal junction cancer (ANGEL study): an international, randomized, placebo-controlled, phase 3 trial.

BACKGROUND: Rivoceranib is an oral, selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. ANGEL (NCT03042611) was a global, randomized, double-blinded, placebo-controlled, phase 3 study evaluating rivoceranib as 3rd-line or ≥4th-line therapy in patients with advanced/metastatic gastric or gastroesophageal junction (GEJ) cancer. METHODS: Patients had failed ≥2 lines of chemotherapy and were randomized 2:1 to rivoceranib 700 mg once daily or placebo with best supportive care. PRIMARY ENDPOINT: overall survival (OS) in the intention-to-treat population. Secondary endpoints: progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) by blinded independent central review (BICR). RESULTS: In total, 460 patients (rivoceranib n = 308, placebo n = 152) were enrolled. OS was not statistically different for rivoceranib versus placebo (median 5.78 vs. 5.13 months; hazard ratio [HR] 0.93, 95% CI 0.74-1.15; p = 0.4724). PFS by BICR (median 2.83 vs. 1.77 months; HR 0.58, 95% CI 0.47-0.71; p < 0.0001), ORR (6.5% vs. 1.3%; p = 0.0119), and DCR (40.3 vs. 13.2%; p < 0.0001) were improved with rivoceranib versus placebo. In patients receiving ≥4th-line therapy, OS (median 6.34 vs. 4.73 months; p = 0.0192) and PFS by BICR (median 3.52 vs. 1.71 months; p < 0.0001) were improved with rivoceranib versus placebo. The most common grade ≥ 3 treatment-emergent adverse events with rivoceranib were hypertension (17.9%), anemia (10.4%), aspartate aminotransferase increased (9.4%), asthenia (8.5%), and proteinuria (7.5%). CONCLUSIONS: This study did not meet its primary OS endpoint. Compared to placebo, rivoceranib improved PFS, ORR, and DCR. Rivoceranib also improved OS in a prespecified patient subgroup receiving ≥4th-line therapy.

Matching-adjusted indirect comparison of amivantamab vs mobocertinib in platinum-pretreated EGFR Exon 20 insertion-mutated non-small-cell lung cancer.

Aim: We assessed relative efficacy and safety of amivantamab versus mobocertinib in patients with non-small-cell lung cancer with EGFR exon 20 insertion (exon20ins) mutations who progressed on prior platinum-based chemotherapy. Materials & methods: This matching-adjusted indirect comparison used patient-level data from CHRYSALIS (NCT02609776) and aggregate data from a mobocertinib trial (NCT02716116) to match populations on all clinically relevant confounders. Results: While both agents had similar efficacy for time-to-event outcomes, objective response rate was significantly higher for amivantamab. 15 of 23 any-grade treatment-related adverse events reported for mobocertinib were significantly less common for amivantamab versus only two for mobocertinib. Conclusion: Results suggest that amivantamab has an improved response rate with similar survival and a more favorable safety profile versus mobocertinib in EGFR exon20ins non-small-cell lung cancer.

7-Amino-[1,2,4]triazolo[1,5-a][1,3,5]triazines as CK1δ inhibitors: Exploring substitutions at the 2 and 5-positions.

CK1δ is a serine-threonine kinase involved in several pathological conditions including neuroinflammation and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Specifically, it seems that an inhibition of CK1δ could have a neuroprotective effect in these conditions. Here, a series of [1,2,4]triazolo[1,5-a][1,3,5]triazines were developed as ATP-competitive CK1δ inhibitors. Both positions 2 and 5 have been explored leading to a total of ten compounds exhibiting IC50s comprised between 29.1 µM and 2.08 µM. Three of the four most potent compounds (IC50 < 3 µM) bear a thiophene ring at the 2 position. All compounds have been submitted to computational studies that identified the chain composed of at least 2 atoms (e.g., nitrogen and carbon atoms) at the 5 position as crucial to determine a key bidentate hydrogen bond with Leu85 of CK1δ. Most potent compounds have been tested in vitro, resulting passively permeable to the blood-brain barrier and, safe and slight neuroprotective on a neuronal cell model. These results encourage to further structural optimize the series to obtain more potent CK1δ inhibitors as possible neuroprotective agents to be tested on models of the above-mentioned neurodegenerative diseases.

Incidence of hand-foot syndrome with protein kinase inhibitors in advanced hepatocellular carcinoma patients who received atezolizumab-bevacizumab combination.

INTRODUCTION: Treatment of advanced HepatoCellular Carcinoma (HCC) is based on first-line (L1) combination of atezolizumab and high-dose (HD) bevacizumab while second-line (L2) refers one antiangiogenic protein kinase inhibitors (aaPKI). This prolonged antiangiogenic pressure let us to observe an increasing occurrence of Hand-Foot Syndromes (HFS) in patients receiving aaPKI after HD bevacizumab combination. This study reports observations and discussions about the evidence and hypothesis that could be made. METHODS: Patients who received the L1 combination from September 1st 2020 to December 31st 2022 to identify L2 aaPKI. Demographic, biological, oncological data and occurrence of HFS were collected. In addition were collected the number of L1 combination cycles, type of aaPKI, and delay between last L1 cycle and L2 initiation. This study had a purely exploratory purpose, so no statistical analysis was planned. RESULTS: 17 patients received an aaPKI after the L1 HD bevacizumab combination with a median time of 26 days from last L1 cycle to L2 start. Five patients experienced HFS including grade 3 (n = 2) with sorafenib and cabozantinib. The HFS occurred with a median delay of 23 days (IQR: 21-28) from aaPKI start. Three patients experienced aaPKI-related dose-limiting toxicity. CONCLUSIONS: Proportion of patients experienced HFS in our cohort did not differ from pivotal trials data and the sample size do not allow to conclude. Hypotheses include timing of aaPKI start in HCC treatment, vascular toxicity at aaPKI start after HD bevacizumab discontinuation instead combination, patient-related outcome for a better understanding of these aaPKI-related HFS post HD bevacizumab.

Prevalence and management of proteinuria associated with vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitor treatment in advanced renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer.

Vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitors (VEGFR-TKIs) are often used for treatment of several types of cancer; however, they are associated with an increased risk of proteinuria, sometimes leading to treatment discontinuation. We searched PubMed and Scopus to identify clinical studies examining the incidence and risk factors for proteinuria caused by VEGFR-TKIs in patients with renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. The global incidence of proteinuria ranged from 6% to 34% for all grades of proteinuria, and from 1% to 10% for grade ≥3 proteinuria. The incidence of proteinuria did not differ significantly by cancer type, but in all three cancer types, there was a trend toward a higher incidence of proteinuria with lenvatinib than with other VEGFR-TKIs. In terms of risk factors, the incidence of proteinuria was significantly higher among Asians (including Japanese) compared with non-Asian populations. Other risk factors included diabetes mellitus, hypertension, and previous nephrectomy. When grade 3/4 proteinuria occurs, patients should be treated according to the criteria for dose reduction or withdrawal specified for each drug. For grade 2 proteinuria, treatment should be continued when the benefits outweigh the risks. Referral to a nephrologist should be considered for symptoms related to decreased renal function or when proteinuria has not improved after medication withdrawal. These management practices should be implemented universally, regardless of the cancer type.

An Assessment of Dispersion-Corrected DFT Methods for Modeling Nonbonded Interactions in Protein Kinase Inhibitor Complexes.

Accurate modeling of nonbonded interactions between protein kinases and their small molecule inhibitors is essential for structure-based drug design. Quantum chemical methods such as density functional theory (DFT) hold significant promise for quantifying the strengths of these key protein-ligand interactions. However, the accuracy of DFT methods can vary substantially depending on the choice of exchange-correlation functionals and associated basis sets. In this study, a comprehensive benchmarking of nine widely used DFT methods was carried out to identify an optimal approach for quantitative modeling of nonbonded interactions, balancing both accuracy and computational efficiency. From a database of 2139 kinase-inhibitor crystal structures, a diverse library of 49 nonbonded interaction motifs was extracted, encompassing CH-π, π-π stacking, cation-π, hydrogen bonding, and salt bridge interactions. The strengths of nonbonded interaction energies for all 49 motifs were calculated at the advanced CCSD(T)/CBS level of theory, which serve as references for a systematic benchmarking of BLYP, TPSS, B97, ωB97X, B3LYP, M062X, PW6B95, B2PLYP, and PWPB95 functionals with D3BJ dispersion correction alongside def2-SVP, def2-TZVP, and def2-QZVP basis sets. The RI, RIJK, and RIJCOSX approximations were used for selected functionals. It was found that the B3LYP/def2-TZVP and RIJK RI-B2PLYP/def2-QZVP methods delivered the best combination of accuracy and computational efficiency, making them well-suited for efficient modeling of nonbonded interactions responsible for molecular recognition of protein kinase inhibitors in their targets.

Novel Phthalic-Based Anticancer Tyrosine Kinase Inhibitors: Design, Synthesis and Biological Activity.

In this work, fragments of isophthalic and terephthalic acids are proposed as a structural scaffold to develop potential inhibitors of protein kinases. Novel isophthalic and terephthalic acid derivatives were designed as type-2 protein kinase inhibitors, synthesized and subjected to physicochemical characterization. The screening of their cytotoxic actions against a panel of cell lines derived from different types of tumors (liver, renal, breast and lung carcinomas, as well as chronic myelogenous and promyelocytic leukemia) and normal human B lymphocyte, for the sake of comparison, was performed. Compound 5 showed the highest inhibitory activity against four cancer cell lines, K562, HL-60, MCF-7 and HepG2 (IC50 = 3.42, 7.04, 4.91 and 8.84 µM, respectively). Isophthalic derivative 9 revealed a high potency against EGFR and HER2, at the levels of 90% and 64%, respectively, being comparable to lapatinib at 10 µM. In general, tumor cell cultures were more sensitive to isophthalic acid derivatives than to terephthalic acid ones. In cell cycle studies, isophthalic analogue 5 showed a pronounced dose-dependent effect, and with the increase in its concentration up to 10.0 µM, the number of living cells decreased to 38.66%, while necrosis reached 16.38%. The considered isophthalic compounds had a similar docking performance to that of sorafenib against the VEGFR-2 (PDB id: 4asd, 3wze). The correct binding of compounds 11 and 14 with VEGFR-2 was validated using MD simulations and MM-GPSA calculations.

Economic evaluation of adjuvant therapy with osimertinib in patients with early-stage non-small cell lung cancer and mutated EGFR.

PURPOSE: The ADAURA trial demonstrated the superiority of osimertinib over a placebo with regard to disease-free survival, showing it to be indicated as an adjuvant therapy for treatment of non-small cell lung cancer with mutated epidermal growth factor receptor (EGFR). The aim of the present study was to conduct a cost-utility analysis and an analysis of the budgetary impact of adjuvant therapy with osimertinib in patients with non-small cell lung cancer with mutated EGFR who had undergone resection surgery with curative intent. METHODS: Analyses were based on the outcomes of the ADAURA clinical trial and were conducted through a Spanish National Health Service perspective. The outcome measures used were quality-adjusted life years (QALY). RESULTS: The average overall cost of adjuvant treatment with osimertinib over a period of 100 months in the overall sample of trial patients (stages IB-IIIA) was 220,961 €, compared with 197,849 € in the placebo group. Effectiveness, estimated according to QALY, was 6.26 years in the osimertinib group and 5.96 years in the placebo group, with the incremental cost-utility ratio being 77,040 €/QALY. With regard to the budgetary impact, it was estimated that, in 2021, approximately 1130 patients would be subsidiaries to receive osimertinib. This pertains to a difference of 17,375,330 € over 100 months to fund this treatment relative to no treatment. CONCLUSION: Taking into account a Spanish threshold of 24,000 €/QALY, the reduction in the acquisition cost of osimertinib will have to be greater than 10%, to obtain a cost-effective alternative.

Inhibition of gingival fibroblast necroptosis mediated by RIPK3/MLKL attenuates periodontitis.

AIM: Necroptosis participates in the pathogenesis of many inflammatory diseases, including periodontitis. Here, we aimed to investigate the role and mechanism of necroptosis inhibitors in attenuating periodontitis. MATERIALS AND METHODS: The Gene Expression Omnibus (GEO) dataset GSE164241 was re-analysed to identify the role of necroptosis in periodontitis. Gingival specimens from healthy subjects or periodontitis patients were collected to evaluate the expression level of necroptosis-associated proteins. The therapeutic effect of necroptosis inhibitors on periodontitis was assessed in vivo and in vitro. Moreover, Transwell assays and Western blotting and siRNA transfection were used to identify the effects of necroptotic human gingival fibroblasts (hGFs) on THP-1 macrophages. RESULTS: Re-analysis revealed that gingival fibroblasts (GFs) in periodontitis gingiva showed the highest area under the curve score of necroptosis. Elevated levels of necroptosis-associated proteins were identified in GFs in periodontitis gingiva collected from patients and mice. In ligature-induced periodontitis mice, local administration of receptor interacting protein kinase 3(RIPK3) inhibitor GSK'872 or sh-mixed-lineage kinase domain-like pseudokinase (Mlkl) markedly abrogated necroptosis and rescued periodontitis. Analogously, necroptosis inhibitors alleviated the inflammatory response and release of damage-associated molecular patterns in lipopolysaccharide- or LAZ (LPS + AZD'5582 + z-VAD-fmk, necroptosis inducer)-induced GFs and then reduced THP-1 cell migration and M1 polarization. CONCLUSIONS: Necroptosis in GFs aggravated gingival inflammation and alveolar bone loss. Necroptosis inhibitors attenuate this process by modulating THP-1 macrophage migration and polarization. This study offers novel insights into the pathogenesis and potential therapeutic targets of periodontitis.

Identification of a new structural family of SGK1 inhibitors as potential neuroprotective agents.

SGK1 is a serine/threonine kinase involved in several neurodegenerative-related pathways such as apoptosis, neuroinflammation, ionic channel regulation, and autophagy, among others. Despite its potential role as a pharmacological target against this kind of diseases, there are no reported inhibitors able to cross the BBB so far, being a field yet to be explored. In this context, a structure-based virtual screening against this kinase was performed, pointing out the deazapurine moiety as an interesting and easy-to-derivatize scaffold. Moreover, these inhibitors are able to i) exert neuroprotection in an in vitro model of AD and ii) block mitophagy in a PRKN-independent manner, reinforcing the hypothesis of SGK1 inhibitors as neuroprotective chemical tools.

Emerging kinase inhibitors for the treatment of pancreatic ductal adenocarcinoma.

INTRODUCTION: Pancreatic cancer is one of the deadliest solid organ cancers. In the absence of specific warning symptoms pancreatic cancer is diagnosed notoriously late. Current systemic chemotherapy regimens extend survival by a mere few months. With the advances in genetic, proteomic, and immunological profiling there is strong rationale to test kinase inhibitors to improve outcome. AREAS COVERED: This review article provides a comprehensive summary of approved treatments and past, present, and future developments of kinase inhibitors in pancreatic cancer. Emerging roles of protein kinase inhibitors are discussed in the context of the unique stroma, the lack of high-prevalence therapeutic targets and rapid emergence of acquired resistance, novel immuno-oncology kinase targets, and recent medicinal chemistry advances. EXPERT OPINION: Due to the to-date frequent failure of protein kinase inhibitors indiscriminately administered to unselected pancreatic cancer patients, there is a shift toward the development of these agents in molecularly defined subgroups which are more likely to respond. The development of accurate biomarkers to select patients who are the best candidates based on a detailed understanding of mechanism of action, pro-survival roles, and mediation of resistance of targeted kinases will be critical for the future development of protein kinase inhibitors in this disease.

Solid Tumors and Kinase Inhibition: Management and Therapy Efficacy Evolution.

The increasing numbers of cancer cases worldwide and the exceedingly high mortality rates of some tumor subtypes raise the question about if the current protocols for cancer management are effective and what has been done to improve upon oncologic patients' prognoses. The traditional chemo-immunotherapy options for cancer treatment focus on the use of cytotoxic agents that are able to overcome neoplastic clones' survival mechanisms and induce apoptosis, as well as on the ability to capacitate the host's immune system to hinder the continuous growth of malignant cells. The need to avert the highly toxic profiles of conventional chemo-immunotherapy and to overcome the emerging cases of tumor multidrug resistance has fueled a growing interest in the field of precision medicine and targeted molecular therapies in the last couple of decades, although relatively new alternatives in oncologic practices, the increased specificity, and the positive clinical outcomes achieved through targeted molecular therapies have already consolidated them as promising prospects for the future of cancer management. In recent years, the development and application of targeted drugs as tyrosine kinase inhibitors have enabled cancer treatment to enter the era of specificity. In addition, the combined use of targeted therapy, immunotherapy, and traditional chemotherapy has innovated the standard treatment for many malignancies, bringing new light to patients with recurrent tumors. This article comprises a series of clinical trials that, in the past 5 years, utilized kinase inhibitors (KIs) as a monotherapy or in combination with other cytotoxic agents to treat patients afflicted with solid tumors. The results, with varying degrees of efficacy, are reported.

Cardiotoxicity Induced by Protein Kinase Inhibitors in Patients with Cancer.

Kinase inhibitors (KIs) represent a growing class of drugs directed at various protein kinases and used in the treatment of both solid tumors and hematologic malignancies. It is a heterogeneous group of compounds that are widely applied not only in different types of tumors but also in tumors that are positive for a specific predictive factor. This review summarizes common cardiotoxic effects of KIs, including hypertension, arrhythmias with bradycardia and QTc prolongation, and cardiomyopathy that can lead to heart failure, as well as less common effects such as fluid retention, ischemic heart disease, and elevated risk of thromboembolic events. The guidelines for cardiac monitoring and management of the most common cardiotoxic effects of protein KIs are discussed. Potential signaling pathways affected by KIs and likely contributing to cardiac damage are also described. Finally, the need for further research into the molecular mechanisms underlying the cardiovascular toxicity of these drugs is indicated.