Current status of drugs targeting PDGF/PDGFR.

As an important proangiogenic factor, platelet-derived growth factor (PDGF) and its receptor PDGFR are highly expressed in a variety of tumors, fibrosis, cardiovascular and neurodegenerative diseases. Targeting the PDGF/PDGFR pathway is therefore a promising therapeutic strategy. At present, a variety of PDGF/PDGFR targeted drugs with potential therapeutic effects have been developed, mainly including PDGF agonists, inhibitors targeting PDGFR and proteolysis targeting chimera (PROTACs). This review clarifies the structure, biological function and disease correlation of PDGF and PDGFR, and it discusses the current status of PDGFR-targeted drugs, so as to provide a reference for subsequent research.

Hematocrit control and thrombotic risk in patients with polycythemia vera treated with ruxolitinib in clinical practice.

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by unregulated red blood cell production resulting in elevated hemoglobin and/or hematocrit levels. Patients often have symptoms such as fatigue, pruritus, and painful splenomegaly, but are also at risk of thrombosis, both venous and arterial. Ruxolitinib, a selective Janus kinase inhibitor, is approved by the US Food and Drug Administration as second-line cytoreductive treatment after intolerance or inadequate response to hydroxyurea. Although ruxolitinib has been widely used in this setting, limited data exist in the literature on ruxolitinib treatment patterns and outcomes among patients with PV in routine clinical practice. We report a retrospective, observational, cohort study of patients treated for PV with ruxolitinib across three US centers (academic and regional practice) from December 2014-December 2019. The study included 69 patients, with a median follow-up duration of 3.7 years (95% CI, 2.9-4.4). Our data demonstrate very high rates of hematocrit control (88% of patients by three months and 89% by six months); few patients required dose adjustments or suspension. No arterial thromboses were observed; however, the follow-up duration does not allow for the generation of meaningful conclusions from this. Three patients had thrombotic events; one was in the setting of a second malignancy, one post-operative, and a third related to prolonged immobility. We also found that 28% of patients initiated ruxolitinib as a result of poorly controlled platelet counts, second only to hydroxyurea intolerance (46%) as a reason to start therapy. In clinical practice, ruxolitinib continues to be effective in controlling hematocrit levels after three and six months of treatment in patients and is associated with low thrombotic risk.

No prognostic impact of staging bone scan in patients with stage IA non-small cell lung cancer.

OBJECTIVE: To investigate the survival benefit of preoperative bone scan in asymptomatic patients with early-stage non-small cell lung cancer (NSCLC). METHODS: This retrospective study included patients with radical resection for stage T1N0M0 NSCLC between March 2013 and December 2018. During postoperative follow-up, we monitored patient survival and the development of bone metastasis. We compared overall survival, bone metastasis-free survival, and recurrence-free survival in patients with or without preoperative bone scan. Propensity score matching and inverse probability of treatment weighting were used to minimize election bias. RESULTS: A total of 868 patients (58.19 ± 9.69 years; 415 men) were included in the study. Of 87.7% (761 of 868) underwent preoperative bone scan. In the multivariable analyses, bone scan did not improve overall survival (hazard ratio [HR] 1.49; 95% confidence intervals [CI] 0.91-2.42; p = 0.113), bone metastasis-free survival (HR 1.18; 95% CI 0.73-1.90; p = 0.551), and recurrence-free survival (HR 0.89; 95% CI 0.58-1.39; p = 0.618). Similar results were obtained after propensity score matching (overall survival [HR 1.28; 95% CI 0.74-2.23; p = 0.379], bone metastasis-free survival [HR 1.00; 95% CI 0.58-1.72; p = 0.997], and recurrence-free survival [HR 0.76; 95% CI 0.46-1.24; p = 0.270]) and inverse probability of treatment weighting. CONCLUSION: There were no significant differences in overall survival, bone metastasis-free survival, and recurrence-free survival between asymptomatic patients with clinical stage IA NSCLC with or without preoperative bone scan.

A nomogram for predicting liver metastasis in patients with gastric gastrointestinal stromal tumor.

BACKGROUND: Liver metastasis (LIM) is an important factor in the diagnosis, treatment, follow-up, and prognosis of patients with gastric gastrointestinal stromal tumor (GIST). There is no simple tool to assess the risk of LIM in patients with gastric GIST. Our aim was to develop and validate a nomogram to identify patients with gastric GIST at high risk of LIM. METHODS: Patient data diagnosed as having gastric GIST between 2010 and 2019 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into training cohort and internal validation cohort in a 7:3 ratio. For external validation, retrospective data collection was performed on patients diagnosed as having gastric GIST at Yunnan Cancer Center (YNCC) between January 2015 and May 2023. Univariate and multivariate logistic regression analyses were used to identify independent risk factors associated with LIM in patients with gastric GIST. An individualized LIM nomogram specific for gastric GIST was formulated based on the multivariate logistic model; its discriminative performance, calibration, and clinical utility were evaluated. RESULTS: In the SEER database, a cohort of 2341 patients with gastric GIST was analyzed, of which 173 cases (7.39%) were found to have LIM; 239 patients with gastric GIST from the YNCC database were included, of which 25 (10.46%) had LIM. Multivariate analysis showed tumor size, tumor site, and sex were independent risk factors for LIM (P < .05). The nomogram based on the basic clinical characteristics of tumor size, tumor site, sex, and age demonstrated significant discrimination, with an area under the curve of 0.753 (95% CI, 0.692-0.814) and 0.836 (95% CI, 0.743-0.930) in the internal and external validation cohort, respectively. The Hosmer-Lemeshow test showed that the nomogram was well calibrated, whereas the decision curve analysis and the clinical impact plot demonstrated its clinical utility. CONCLUSIONS: Tumor size, tumor subsite, and sex were significantly correlated with the risk of LIM in gastric GIST. The nomogram for patients with GIST can effectively predict the individualized risk of LIM and contribute to the planning and decision making related to metastasis management in clinical practice.

The underlying roles and neurobiological mechanisms of music-based intervention in Alzheimer's disease: A comprehensive review.

Non-pharmacological therapy has gained popularity in the intervention of Alzheimer's disease (AD) due to its apparent therapeutic effectiveness and the limitation of biological drug. A wealth of research indicates that music interventions can enhance cognition, mood and behavior in individuals with AD. Nonetheless, the underlying mechanisms behind these improvements have yet to be fully and systematically delineated. This review aims to holistically review how music-based intervention (MBI) ameliorates abnormal emotion, cognition decline, and behavioral changes in AD patients. We cover several key dimensions: the regulation of MBIs on cerebral blood flow (CBF), their impact on neurotransmission (including GABAergic and monoaminergic transmissions), modulation of synaptic plasticity, and hormonal release. Additionally, we summarize the clinical applications and limitations of active music-based intervention (AMBI), passive music-based intervention (PMBI), and hybrid music-based intervention (HMBI). This thorough analysis enhances our understanding of the role of MBI in AD and supports the development of non-pharmacological therapeutic strategies.

Effects of volume-matched acute exercise on metacognition in late middle-aged adults: The roles of exercise intensity and duration.

Increasing studies have observed the benefit of acute exercise on core executive functions (EFs). However, the effects of high-order EFs (i.e., metacognition) are poorly investigated. Additionally, the beneficial effect varies depending on exercise-related variables (e.g., intensity, duration). Exercise volume, represented by exercise intensity and duration, is one approach to examine the relationship between acute exercise and metacognition. Therefore, this study aims to investigate the effects of acute exercise, involving three volume-matched evaluations, on metacognition in late middle-aged adults. It recruited 40 community-dwelling late middle-aged adults (22 females; Mage=61.05±4.17years). Its counterbalanced and repeated-measure experimental design included a control reading session and three exercise sessions: (1) acute moderate-intensity exercise for 30min, (2) higher-intensity exercise for 16min, and (3) lower-intensity exercise for 40min. After each session, all participants were asked to perform the Tower of London (TOL) task to assess their metacognition related to planning and problem-solving. This study showed that regardless of exercise intensity and duration variation, acute exercise led to higher move-related (i.e., total correct and move scores) and time-related (i.e., total executive and problem-solving times) scores but did not affect total initial time and violation-related scores compared to reading treatment. These findings suggest enhanced performance in metacognition after acute exercise regardless of its intensity and duration variation.

Transcutaneous Auricular Vagus Nerve Stimulation Alleviates Monobenzone-Induced Vitiligo in Mice.

Vitiligo is a complex skin disorder that involves oxidative stress and inflammatory responses and currently lacks a definitive cure. Transcutaneous auricular vagus nerve stimulation (taVNS) is a noninvasive method for targeting the auricular branch of the vagus nerve and has gained widespread attention for potential intervention in the autonomic nervous system. Although previous research has suggested that vagus nerve stimulation can potentially inhibit inflammatory responses, its specific role and mechanisms in vitiligo treatment remain unknown. This study aimed to explore the therapeutic effects of taVNS in a mouse model of vitiligo induced by monobenzone. Initially, a quantitative assessment of the treatment effects on vitiligo mice was conducted using a scoring system, revealing that taVNS significantly alleviated symptoms, particularly by reducing the depigmented areas. Subsequent immunohistochemical analysis revealed the impact of taVNS treatment on melanocyte granules, mitigating pigment loss in the skin of monobenzone-induced vitiligo mice. Further analysis indicated that taVNS exerted its therapeutic effects through multiple mechanisms, including the regulation of oxidative stress, enhancement of antioxidant capacity, promotion of tyrosine synthesis, and suppression of inflammatory responses. The conclusions of this study not only emphasize the potential value of taVNS in vitiligo therapy, but also lay a foundation for future research into the mechanisms and clinical applications of taVNS.

Photochemical Transformation of Dissolved Organic Matter in Surface Water Augmented the Formation of Disinfection Byproducts.

Sunlight may lead to changes in disinfection byproducts (DBPs) formation potentials of source water via transforming dissolved organic matter (DOM); however, the underlying mechanisms behind these changes remain unclear. This work systematically investigated the effect of photochemical transformation of DOM from reservoir water (DOMRe) and micropolluted river water (DOMRi) after 36 h of simulated sunlight irradiation (equivalent to one month under natural sunlight) on DBPs formation. Upon irradiation, high molecular weight (MW) and aromatic molecules tended to be mineralized or converted into low-MW and highly oxidized (O/C > 0.5) ones which might react with chlorine to generate high levels of DBPs, resulting in an elevation in the yields (µg DBP/mg C) of almost all the measured DBPs and the quantities of unknown DBPs in both DOM samples after chlorination. Additionally, DOMRi contained more aromatic molecules susceptible to photooxidation than DOMRe. Consequently, irradiated DOMRi exhibited a greater increase in the formation potentials of haloacetonitriles, halonitromethanes, and specific regulated DBPs, with nitrogenous DBPs being responsible for the overall rise in the calculated cytotoxicity following chlorination. This work emphasized the importance of a comprehensive removal of phototransformation products that may serve as DBPs precursors from source waters, especially from micropolluted source waters.

Radiotherapy and Anrotinib in Malignant Glomus Tumor of the Bladder: A Case Report and Literature Review.

Background: Malignant glomus tumors (MGTs) are rare malignancies, which grow rapidly and are aggressive. Surgical resection has been regarded as the standard management, but treatment options for those unresectable tumors are limited, resulting in a high recurrence rate and poor prognosis. Case Description: An 85-year-old man presented with gross hematuria and was diagnosed with MGTs of bladder. The patient achieved long-term local control after multimodal therapy comprising radiotherapy, iodine-125 seeds brachytherapy, transcatheter arterial chemoembolization, and antiangiogenic targeted therapy. Conclusion: MGTs occurring in the bladder are clinically rare and refractory. The case presented here highlights the importance of multidisciplinary diagnosis and treatment, providing evidence that radiotherapy and antiangiogenic therapy may play an important role in unresectable bladder MGT.

[Optimization of processing technology of bark of Ilicis Rotundae Cortex based on quality by design concept].

Based on the concept of quality by design(QbD), this study optimized the processing technology of Ilicis Rotundae Cortex. According to the processing method and ingredient requirements of Ilicis Rotundae Cortex in the Chinese Pharmacopoeia, the content of syringin and pedunculoside, alcohol extract, fragmentation rate, and moisture content were taken as the critical quality attributes(CQAs). The soaking time, moistening time, and drying time were taken as critical process parameters(CPPs) by single factor tests. The weight coefficients of CQAs were determined by the analytic hierarchy process(AHP)-entropy weighting method, and the comprehensive score was calculated. With the comprehensive score as the response value, Box-Behnken design was employed to establish a mathematical model between CPPs and CQAs, and the design space for the processing of Ilicis Rotundae Cortex was built and verified. The results of ANOVA showed that the mathematical model had the P value below 0.05, the lack of fit greater than 0.05, adjusted R~2=0.910 5, and predicted R~2=0.831 0, which indicated that the proposed model had statistical significance and good prediction performance. Considering the factors in production, the best processing conditions of Ilicis Rotundae Cortex were decoction pieces of about 1 cm soaking for 1 h, moistening for 4 h, and drying at 60-70 ℃ in a blast drier for 2 h. The optimized processing technology of Ilicis Rotundae Cortex was stable and feasible, which can provide a reference for the standardized preparation and stable quality of Ilicis Rotundae Cortex.

Exploring the chemical components of Kuanchang-Shu granule and its protective effects of postoperative ileus in rats by regulating AKT/HSP90AA1/eNOS pathway.

BACKGROUND: Postoperative ileus (POI) is a common obstruction of intestinal content passage caused by almost all abdominal operations that seriously strokes the quality of life of patients. Kuanchang-Shu granule (KCSG), a classic modified prescription based on "Da-Cheng-Qi Decoction", has obtained satisfactory efficacy in the clinical therapeutics of POI. However, its material basis and holistic molecular mechanism against POI have not been revealed. METHODS: The chemical ingredients of KCSG were first characterized by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Subsequently, an integration strategy of the network pharmacology and molecular docking based on above identified ingredients was performed to unveil the potential targets involved in the treatment of KCSG on POI. Finally, intestinal manipulation induced rat POI model was constructed to verify the efficacy and predicted mechanism of KCSG against POI. RESULTS: In total, 246 ingredients mainly including organic acids, flavonoids, quinones, alkaloids, terpenoids, phenylpropanoids and phenols were identified. 41 essential ingredients, 24 crucial targets as well as 15 relevant signaling pathways were acquired based on network pharmacology analysis. Pharmacodynamic research showed that KCSG treatment could protect intestinal histological damage, promote the recovery of measurement of gastrointestinal transit disorder and inhibit the secretion of myeloperoxidase in the distal ileum tissues. The up-regulated expression of p-AKT and down-regulated expression of p-eNOS and HSP9OAA1 predicted by molecular docking and validated by western blotting showed that AKT/eNOS/HSP90AA1 pathway may be one of the crucial mechanisms that mediates the protective effect of KCSG.

Novel multiplexed alkali enzyme lysis coupled with EDTA pretreatment for RNA virus extraction from wastewater sludge: Optimization, recovery, and detection.

RNA viruses are readily enriched in wastewater sludge owing to adsorption by extracellular polymeric substances (EPS) during wastewater treatment, causing pathogenicity. However, conventional wastewater extraction methods often fail to fully extract these viruses from sludge. In this study, three methods: enzymatic (ENP), alkaline (ALP), and ethylenediaminetetraacetic acid (EDTA) pretreatments were applied to sludges and promote the RNA virus extraction from sludge. Our results show that the total recovery rate of RNA viruses increased by 87.73% after ENP pretreatment, whereas ALP pretreatment inhibited virus extraction. The highest recovery rate of viruses from sludge, reaching 296.80%, was achieved with EDTA pretreatment (EDP) coupled with ENP. Notably, the most significant increase was observed in the abundance of Astroviruses, which increased from 7.60 × 107 to 7.86 × 108 copies/g TSS after EDP + ENP treatment. Our investigations revealed that virus extraction was affected by a class of short-wavelength protein substances, as opposed to tryptophan or tyrosine, which were eluted by proteins with beef paste buffer by substitution after EDP + ENP treatment. The results of this study provide essential insights for sludge-based epidemiology with the required sensitivity for managing the extraction of RNA epidemic viruses to control viral transmission.

Discovery, Optimization, and Evaluation of Novel Pyridin-2(1H)-one Analogues as Potent TRK Inhibitors for Cancer Treatment.

Tropomyosin receptor kinase (TRK) fusion, an oncogenic form of kinase with pan-tumor occurrence, is a clinically validated important antitumor target. In this study, we screened our in-house kinase inhibitor library against TRK and identified a promising hit compound 4 with a novel pyridin-2(1H)-one scaffold. Through a combination of structure-based drug design and structure-activity relationship (SAR) study, compound 14q was identified as a potent TRK inhibitor with good kinase selectivity. It also blocked cellular TRK signaling, thereby inhibiting TRK-dependent cell viability. Additionally, 14q displayed acceptable pharmacokinetic properties with 37.8% oral bioavailability in mice. Strong in vivo tumor growth inhibition of 14q was observed in subcutaneous M091 and KM12 tumor xenograft models with TRK fusion, causing significant tumor inhibition or even complete tumor regression.

Discovery of hematopoietic progenitor kinase 1 inhibitors using machine learning-based screening and free energy perturbation.

Hematopoietic progenitor kinase 1 (HPK1) is a key negative regulator of T-cell receptor (TCR) signaling and a promising target for cancer immunotherapy. The development of novel HPK1 inhibitors is challenging yet promising. In this study, we used a combination of machine learning (ML)-based virtual screening and free energy perturbation (FEP) calculations to identify novel HPK1 inhibitors. ML-based screening yielded 10 potent HPK1 inhibitors (IC50 < 1 µM). The FEP-guided modification of the in-house false-positive hit, DW21302, revealed that a single key atom change could trigger activity cliffs. The resulting DW21302-A was a potent HPK1 inhibitor (IC50 = 2.1 nM) and potently inhibited cellular HPK1 signaling and enhanced T-cell function. Molecular dynamics (MD) simulations and ADME predictions confirmed DW21302-A as candidate compound. This study provides new strategies and chemical scaffolds for HPK1 inhibitor development.Communicated by Ramaswamy H. Sarma.

Breaking CHIPS-Mediated immune evasion with tripterin to promote neutrophil chemotaxis against MRSA infection.

Neutrophils are the most important innate immune cells in host defense against methicillin-resistant Staphylococcus aureus (MRSA). However, MRSA orchestrates precise and timely expression of a series of virulence factors, especially the chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS), to evade neutrophil-mediated host defenses. Here, we demonstrated that tripterin, a plant-derived bioactive pentacyclic triterpenoid, had a low minimum inhibitory concentration (MIC) of 1.28 µg/mL and displayed excellent anti-MRSA activity in vitro and in vivo. RNA-seq and further knockdown experiments revealed that tripterin could dramatically downregulate the expression of CHIPS by regulating the SaeRS two-component regulatory system, thereby enhancing the chemotactic response of neutrophils. Furthermore, tripterin also displayed a potential inhibitory effect on biofilm components to enhance neutrophil infiltration into the interior of the biofilm. In a mouse bacteremia model, tripterin could still maintain an excellent therapeutic effect that was significantly better than that of the traditional antibiotic vancomycin. Overall, these results suggest that tripterin possesses a superior antibacterial activity via breaking CHIPS-mediated immune evasion to promote neutrophil chemotaxis, thus providing a novel strategy for combating serious pathogenic infections.

MicroRNA-195 liposomes for therapy of Alzheimer's disease.

The complex etiologies and mechanisms of Alzheimer's disease (AD) underscore the importance for devising multitarget drugs to achieve effective therapy. MicroRNAs (miRNAs) are capable of concurrently regulating the expression of multiple proteins by selectively targeting disease- associated genes in a sequence-specific fashion. Nonetheless, as RNA-based drugs, their stability in the circulation and capacity of traversing the blood-brain barrier (BBB) is largely compromised, thereby limiting their potential clinical applications. In this study, we formulated the nanoliposomes encapsulating polyethyleneimine (PEI)/miR-195 complex (DPMT@PEI/miR-195) that was engineered through dual modifications to contain P-aminophenyl-alpha-d-mannopyranoside (MAN) and cationic cell-penetrating peptide (TAT). DPMT@PEI/miR-195 exhibited the enhanced BBB- and cell membrane penetrating capability. As expected, we observed that DPMT@PEI/miR-195 administered through intravenous tail injection of produced greater effectiveness than donepezil and the same range of effect as aducanumab in alleviating the cognitive decline in 7-month-old APP/PS1 mice. Moreover, the combination treatment with DPMT@PEI/miR-195 and donepezil effectively ameliorated the deterioration of cognition in 16-month-old APP/PS1 mice, with enhanced effects than either DPMT@PEI/miR-195 or donepezil alone. Furthermore, DPMT@PEI/miR-195 effectively attenuated the positive signals of Aß, AT8, and CD68 in APP/PS1 mice without notable side effects. Our findings indicate DPMT@PEI/miR-195 as a promising potentially new agent or approach for the prophylaxis and treatment of early and advanced stages of Alzheimer's disease.

Development and experimental validation of a machine learning-based disulfidptosis-related ferroptosis score for hepatocellular carcinoma.

Disulfidoptosis and ferroptosis are two distinct programmed cell death pathways that have garnered considerable attention due to their potential as therapeutic targets. However, despite their significance of these pathways, the role of disulfidoptosis-related ferroptosis genes in hepatocellular carcinoma (HCC) remains unclear. In this study, we employed a comprehensive approach that utilized various sophisticated techniques such as Pearson analysis, differential analysis, uniCox regression, lasso, ranger, and multivariable Cox regression to develop the disulfidoptosis-related ferroptosis (DRF) score. We then classified patients with HCC into high- and low-score groups to examine the association between the DRF score and various outcomes, including prognosis, functional enrichment, immune infiltration, immunotherapy, TACE sensitivity, drug sensitivity, and single-cell level function. Finally, we conducted in vitro experiments to validate the function of KIF20A. Our analysis revealed that KIF20A, G6PD, SLC7A11, and SLC2A1 were integral to constructing the DRF score. Our findings showed that patients with low DRF scores had significantly better prognoses and were more responsive to immunotherapy, TACE, and chemotherapy than those with high DRF scores. Based on our results obtained from bulk RNA-seq, single-cell RNA-seq, and in vitro experiments, we identified the cell cycle pathway as the primary distinguished factor between high-score and low-score groups. This study sheds light on the contribution of disulfidoptosis-related ferroptosis genes to the development and progression of HCC. The information gleaned from this study can be leveraged to improve our understanding of their potential as therapeutic targets for HCC treatment.

Acute Exercise Effect on Neurocognitive Function Among Cognitively Normal Late-Middle-Aged Adults With/Without Genetic Risk of AD: The Moderating Role of Exercise Volume and APOE Genotype.

BACKGROUND: Acute exercise is a behavior that benefits cognitive function; however, its effect on populations with different risks for Alzheimer's disease (AD) and the role of exercise variance and Apolipoprotein E (APOE) genotype on this effect remains unknown. This study explores the acute exercise effect on behavioral and neurocognitive function, and its potential moderation by exercise intensity and duration and APOE genetic risk. METHODS: Fifty-one cognitively normal adults (~36% APOE ε4 carriers) performed the Stroop task under a rest condition and 3 exercise conditions while electroencephalographic activity was assessed. RESULTS: Acute exercise improved cognitive performance assessed through both behavioral and neuroelectrical indices. These benefits were observed regardless of adjustments of intensity and duration at a predetermined exercise volume as well as being evident irrespective of APOE ɛ4 carrier status. CONCLUSIONS: Acute exercise could be proposed as a lifestyle intervention to benefit neurocognitive function in populations with and without genetic risk of AD. Future exploration should further the precise exercise prescription and also the mechanisms underlying the beneficial effects of acute exercise for neurocognitive function. CLINICAL TRIALS REGISTRATION NUMBER: NCT05591313.

Discovery of a 1,6-naphthyridin-4-one-based AXL inhibitor with improved pharmacokinetics and enhanced in vivo antitumor efficacy.

The receptor tyrosine kinase AXL has emerged as an attractive target in anticancer drug discovery. Herein, we described the discovery of a new series of 1,6-naphthyridin-4-one derivatives as potent AXL inhibitors. Starting from a low in vivo potency compound 9 which was previously reported by our group, we utilized structure-based drug design and scaffold hopping strategies to discover potent AXL inhibitors. The privileged compound 13c was a highly potent and orally bioavailable AXL inhibitor with an IC50 value of 3.2 ± 0.3 nM. Compound 13c exhibited significantly improved in vivo antitumor efficacy in AXL-driven tumor xenograft mice, causing tumor regression at well-tolerated dose, and demonstrated favorable pharmacokinetic properties (MRT = 16.5 h, AUC0-∞ = 59,815 ng h/mL) in Sprague-Dawley rats. These results suggest that 13c is a promising therapeutic candidate for AXL-targeting cancer treatment.

Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors.

As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC50: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC50: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.