Design, synthesis, and in silico study of VEGFR-2 and HDAC dual acting quinazoline based molecules for anticancer evaluation.

Design, synthesis, and mechanistic study of bispecific small molecules-based phenyl pyrazolopyrimidinone scaffold as dual-targeting VEGFR and PD-L1 immune checkpoint in hepatocellular carcinoma.

Applying artificial intelligence and machine learning framework for de novo design of pyrazole-based VEGFR-2 inhibitors.

Design and synthesis of benzofuran-pyrazole hybrids as dual TGF-βR1/VEGFR-2 inhibitors for anticancer applications

Dragon's blood and its active components ameliorate pressure overload-induced heart failure via remodeling of cardiac lymphatics.

In this study, two series of VEGFR-2 inhibitors were designed based on the Fruquintinib and Cabozantinib. Series 1 compounds retained the quinazoline skeleton and amide group of Fruquintinib, while the benzofuran moiety was replaced with a coumarin moiety, and various substituents were introduced at the amide N-terminus to explore structure-activity relationships (SARs). Series 2 compounds were derived from Cabozantinib by incorporating a rigid pyridine linker via conformational constraint and replacing the terminal phenyl group with bicyclo[1.1.1]pentane (BCP). All target compounds were evaluated for their VEGFR-2 inhibitory activity. Among series 1, compound 20 showed the significant inhibitory activity with an IC₅₀ value of 85.35nM. Notably, series 2 compounds demonstrated significantly improved potency, with IC50 values below 30nM. Compound 32 was the most potent VEGFR-2 inhibitor with an IC50 value of 7.52nM, while its IC50 values for VEGFR-1 and VEGFR-3 were 74.41 and 5.63nM, respectively. In vitro antiproliferative assays revealed that several series 2 compounds, including 32, displayed more potent antiproliferative activity against A549 cells than Cabozantinib. Molecular docking studies elucidated the binding mode of compound 32, highlighting key hydrogen bond with the hinge region of VEGFR-2. Collectively, compound 32 emerges as a promising lead compound for further optimization as a novel VEGFR-2 inhibitor.

Primary resistant disease (PRD) to immuno-oncology plus vascular endothelial growth factor receptor inhibitor (IOVE) therapy is a critical unmet need in metastatic renal cell carcinoma (mRCC), yet its clinical and molecular features remain poorly defined. We provide the first integrated clinical and genomic characterization of PRD, combining two complementary, non-overlapping cohorts: a real-world clinical cohort of 159 patients (Hiroshima Cancer Registry Project, H-CARP) and a national genomic database (Center for Cancer Genomics and Advanced Therapeutics, C-CAT). PRD (n = 20 [12.6%]) defined a distinct high-risk group with markedly shorter progression-free survival, PFS2, and overall survival (OS) and a median OS of 8.5 months. Notably, liver metastasis was a strong, readily available independent predictor of PRD (odds ratio 4.99; p = 0.011), enabling early risk stratification, and non-clear cell histology was enriched among PRD. The comparable OS with or without subsequent therapy underscores an urgent need for novel strategies. Exploratory genomic profiling revealed candidate, hypothesis-generating correlates of resistance (lower VHL and PBRM1; higher TSC2 and MSH3 alterations). By linking real-world outcomes with national genomic data, this study establishes a foundation for early identification and biomarker-guided management of PRD.

KRAS mutations are significant drivers in various cancers, and existing drug discovery attempts targeting these mutations have largely been unsuccessful, emphasizing the need for more effective therapies. In this study, the screening library, which contains 1,374 chemical compounds, identified nintedanib, a VEGFR inhibitor, as exerting a potent and selective antiproliferative effect against KRAS-mutant cells, surpassing other VEGFR inhibitors. Nintedanib effectively suppressed tumor growth in xenografted mice with KRAS mutations and significantly inhibited phosphorylated VEGFR2 levels and its downstream signaling molecules pAKT and pERK in KRAS-mutant cells, suggesting that VEGFR2 inhibition affects the oncogenic AKT/ERK pathway. Moreover, in VEGFR2-knockout cells, inhibition of SOS1 protein reduced KRAS-GTP activity, which decreased the phosphorylation of ERK, AKT, and DRP1, thereby inducing apoptosis. Remarkably, KRASG12D overexpression augmented VEGFR2 expression, establishing a positive feedback loop between KRAS mutations and VEGFR2 signaling within the ERK pathway. Immunohistochemical analyses of pancreatic cancer tissues revealed high VEGFR2 expression in 83% (67/80) of samples, significantly exceeding the levels observed in normal pancreatic tissues. These results underscore VEGFR2 as a promising molecular target and propose a novel therapeutic avenue for KRAS-mutant cancers.

VEGFR2 inhibition potentiates STING-mediated antitumor immunity.

Discovery of potent Type-II GSK-3β/VEGFR2 inhibitors with promising potential against tongue squamous cell carcinoma.

4183 Background: High grade neuroendocrine neoplasms (HG-NENs) are treated with platinum doublets mirroring guidelines for small cell lung cancer (SCLC) but recurrences are common and salvage options are limited in efficacy. Cabozantinib (CABO), an inhibitor of VEGFR, MET, and TAM kinases (TYRO3, AXL, and MER) was approved by the FDA for treatment of well differentiated (WD) NENs of both pancreatic and extrapancreatic origins based on the CABINET study (Chan, NEJM 2025). However, its efficacy in the whole spectrum of HG-NEN patients including poorly differentiated disease (PDD) has not been prospectively explored. Methods: This was a single institution, Phase II study of CABO in patients with HG-NENs who had progressed on at least one prior treatment. Key inclusion/exclusion criteria were NENs of any origin except SCLC, high grade by Ki-67 of > 20% or histology consensus, ECOG of < = 1, appropriate hematological parameters and no history of bleeding or active cardiac disease. CABO was given orally starting at 60 mg po daily in 3-week cycles. The primary endpoint of this study was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). A Simon optimal 2-stage design tested the null hypothesis that the true ORR is < = 1% at the type I error rate of 5%, resulting in projected enrollment of up to 32 total patients. Toxicities were graded according to CTCAE v5.0 and response was evaluated according to RECIST v1. Results: All patients have been accrued, with 4/32 patients still on treatment. Median age at diagnosis was 62 years and male to female ratio was 1.46. Origin of tumor was GI in 68.8% of the cases, the rest being thoracic (6.3%), prostate (6.3%) cervical (6.3%) head/neck (3.1%) and unknown (9.4%). Median Ki-67 was 55%, 11 patients had Ki-67 > 70%. Histology was WD-HG in 40% of patients and PDD in 60%. Two patients had mixed PDD/other components (MiNEN). Median PFS in evaluable patients was 4.01 months [95% CI 1.61 to 9.30] and mOS was 9.89 mo [95% CI 6.73 to 18.96]. Three patients so far (9.3%) have had partial response as best response (PDD-colon, WD-pancreas and PDD-cervical) while 19/32 (59.4%) patients have had stable disease as best response so far (disease control rate 68.8%). Five (15.6%) patients have received more than 10 treatment cycles. The three longest treated patients had WD-pancreas (23 and 17 cycles) and PDD-unknown (12 cycles). One patient had eventual resection of a metastatic site and is currently without evidence of disease. Three patients withdrew from the trial because of toxicities (shortness of breath, GI bleeding, thromboembolism). Twenty-six patients have expired. Conclusions: CABO monotherapy showed efficacy in some HG-NEN patients with not just WD but also the very aggressive PDD histology. No new side effects to the ones previously described for this agent were noted. Supported by Exelixis and a Siteman investment program grant. Clinical trial information: NCT04412629 .

FRUQUITAS trial: Study design of an ENGIC intergroup randomized phase III of trifluridine/tipiracil +/- fruquintinib in pre-treated metastatic gastro-oesophageal adenocarcinoma.

Combined experimental and computational investigation of a novel naphthalene-based VEGFR-2 inhibitor with nonlinear optical activity

Targeting VEGFR-2 with piperazine bridged indolin-2-one derivatives.

Narrowing of glioma vascular caliber via chronic VEGFR2 blockade improves the uniformity of focused ultrasound-mediated small molecule drug delivery.

Spinal ependymomas (SE) account for 10% of ependymomas and are the most frequent spinal glial tumors. NF2-related Schwannomatosis (NF2-SWN) patients are predisposed to multiple SE in addition to other tumors, schwannomas and meningiomas. Surgery remains the main treatment option, but mays lead to severe morbidity. In many cases, it is thecystic rather than the solid componentof the tumor that drives neurological symptoms and ultimately necessitates surgical intervention. Understanding tumor and associated cyst formation is therefore important to develop new therapeutic approaches. This clinical and radiological study includes 33 NF2-SWN with a long-term follow-up and 11 sporadic SE patients. Tumor and cyst characteristics were assessed, and histopathological analyses performed, including multiplex immunohistochemistry and RNA sequencing. Radiological analysis revealed that peritumoral edema frequently precedes cystic formation. Histological analysis showed that macrophage infiltration, particularly by SPP1-positive macrophages, was associated with cystic growth in NF2-SWN SE. RNAseq analysis identified distinct immune microenvironments differentiating NF2-SWN from sporadic SE, including differences in VEGF-C expression. Consistent with these results, AXITINIB, a selective inhibitor of VEGFR and VEGFR3 which acts as the receptor for VEGF-C, was proposed to a NF2-SWN patient with a progressing cystic SE and resulted in clinical improvement accompanied by a reduction in the peritumoral cyst. These results support a role for VEGF signaling and macrophage-mediated microenvironmental changes in edema and cystic growth of NF2-SWN SE. The observed clinical response to AXITINIB in an index patient suggests that new combinations of anti-angiogenic therapies may represent a promising early targeted approach.

The high prevalence of depression and limitations of current antidepressants necessitate alternative therapies. Electroacupuncture (EA) shows promise, but its mechanisms remain unclear. Hippocampal impairment in depression involves neuroinflammation linked to defective autophagy. This study investigated whether EA alleviates depressive-like behaviors by enhancing autophagy via the VEGF/AKT1/ERK pathway to attenuate hippocampal neuroinflammation. Bioinformatic analysis of the GEO dataset GSE53987 was performed to identify autophagy- and neuroinflammation-related differentially expressed genes in depression. A chronic unpredictable mild stress (CUMS) rat model was used for validation. Rats were divided into control, CUMS, EA, EA + VEGFR2 inhibitor (SU5416) (EA+SU5416), EA + 3-methyladenine (3-MA), and FXL (fluoxetine) groups. Comprehensive assessments included behavioral tests, Nissl staining for histomorphology, transmission electron microscopy (TEM) for neuronal ultrastructure, immunofluorescence(IF), immunohistochemistry (IHC), Western blot (WB), enzyme-linked immunosorbent assay (ELISA), and reverse transcription quantitative polymerase chain reaction (RT-qPCR) to evaluate therapeutic effects and hippocampal alterations, focusing on VEGF/AKT1/ERK pathway expression and phosphorylation. AKT1 was identified as a key gene linking autophagy and inflammation. CUMS rats exhibited upregulation of hippocampal AKT1 transcription but decreased phosphorylation, along with enrichment of the VEGF pathway. EA at LI4/LR3 significantly ameliorated depressive-like behaviors and hippocampal damage in CUMS rats. Mechanistically, EA upregulated hippocampal VEGF expression and promoted synergistic phosphorylation of AKT1 and ERK. This was accompanied by enhanced autophagic activity (increased LC3-II/I ratio, decreased p62) and attenuated neuroinflammation (reduced IL-1β, TNF-α). Co-administration of the VEGFR2 inhibitor SU5416 largely abolished these therapeutic effects, including behavioral improvement, AKT1/ERK phosphorylation, autophagy enhancement, and anti-neuroinflammation. Furthermore, the autophagy inhibitor 3-MA also blocked EA's benefits, indicating autophagy as the essential downstream executor. EA ameliorated depressive-like behaviors in CUMS rats, suggesting that the mechanism may involve the activation of the VEGF/AKT1/ERK pathway, leading to enhanced autophagy and attenuated hippocampal neuroinflammation.

Chemotherapy remains a cornerstone therapeutic approach for gastric cancer (GC). However, the clinical efficacy of docetaxel is substantially limited by the emergence of drug resistance. Here, we discovered a novel DDR1/VEGFR2 inhibitor, K-13, and further confirmed its selectivity by comprehensive kinase profiling in vitro. Through screening of K-13 in combination with conventional chemotherapeutic agents in GC, we identified a pronounced synergistic effect between K-13 and docetaxel. The combination therapy demonstrated significant antitumor effects in GC cell lines, human GC patient-derived organoids (PDOs), human GC acquired docetaxel-resistant PDOs, subcutaneous xenograft models, and patient-derived xenograft (PDX) models. Mechanistically, K-13 synergized with docetaxel to inhibit Ribonucleotide Reductase M2 (RRM2) to block the AKT/mTOR pathway to reverse resistance and induce ferroptosis, evidenced by mitochondrial alterations, lipid Reactive Oxygen Species (ROS), Malondialdehyde accumulation (MDA), and iron overload. These findings were consistently validated across all preclinical models. The translational potential of this strategy is currently being evaluated in an ongoing phase Ib/II clinical trial, and two partial responses (PRs) have already been observed in patients receiving the combination therapy. These findings underscore dual inhibition of DDR1 and VEGFR2 as a promising therapeutic approach to overcome docetaxel resistance in GC. Graphical abstract: Targeting the dual inhibition of DDR1 and VEGFR2 provides a promising therapeutic strategy to overcome docetaxel resistance in GC. The combination potently inhibited tumor growth across cell lines, PDOs, and PDX models by suppressing RRM2 and blocking AKT/mTOR signaling, ultimately inducing ferroptosis. The translational potential of this strategy is being evaluated in an ongoing phase Ib/II clinical trial, and two partial responses (PRs) have already been observed in patients receiving the combination therapy.

Background and purpose:Angiogenesis, regulated by vascular endothelial growth factor receptor 2 (VEGFR-2), has a key role in tumor progression, especially in common cancers, including colorectal and renal cancer. Inhibiting VEGFR-2 is a promising therapeutic approach. This research aimed to design, synthesize, and biologically evaluate new 5-(pyridine-3-yl)-1,3,4-oxadiazole derivatives as potential VEGFR-2 inhibitors.Experimental approach:A new series of derivatives (AM3-AM6) was synthesized through S-alkylation of 5-(pyridin-3-yl)-1,3,4-oxadiazole-2-thiol and hydrazinolysis reactions, followed by condensation with aldehydes. The compounds were analyzed using FT-IR,1H-NMR, and 13C-NMR spectroscopy. Molecular modelling studies, including docking (PDB ID: 4ASD), ADMET prediction, and molecular dynamics (MD) simulations, were performed to evaluate binding affinity, pharmacokinetic properties, and complex stability. Cytotoxicity was assessed via MTT assay against HT-29 (colorectal), ACHN (renal), and L929 (normal) cell lines.Findings/Results:Docking results revealed strong binding to VEGFR-2, with compound AM3 showing the best docking score (ΔG = -11.613 kcal/mol). MD simulations confirmed the high stability of the AM3-VEGFR-2 complex with consistent RMSD values and persistent interactions with GLU885 and ASP1046. In vitro, AM4 exhibited a significant cytotoxic effect against HT-29 cells (IC50 = 38.94 μM), compared to sorafenib (IC50 = 9.73), while all compounds were non-toxic toward L929 cells.Conclusions and implications:In silico and in vitro results demonstrated that the new 5-(pyridine-3-yl)-1,3,4-oxadiazole derivatives possess favorable drug-like properties and selective anti-proliferative activity against colorectal and renal cancer cells. These findings suggest that this scaffold is a valuable starting point for developing novel selective VEGFR-2 inhibitors as anticancer agents.

Qin Bing eye drops, a traditional Chinese medicine-based in-hospital preparation, were historically indicated for the treatment of conjunctivitis, keratitis, and photokeratitis. This study aimed to develop Qin Pi extract (QP-E) using a proprietary extraction method, and to evaluate the therapeutic efficacy of QP-E alone, QP-E combined with Bing Pian (BP), and an ophthalmic formulation (QP-D) comprising both constituents in a preclinical model of dry eye disease (DED). DED was induced in mice via subcutaneous scopolamine administration alone, whereas a more robust dry eye phenotype was established in rats through combined treatment with scopolamine and environmental stressors. Ocular surface evaluation included measurement of tear secretion volume and corneal fluorescein staining scores. The results demonstrated that both QP-E monotherapy and the QP-E–BP combination significantly ameliorated key pathological features of DED, including tear film instability and corneal epithelial damage. QP-D—formulated with rationally optimized concentrations of QP-E and BP—significantly enhanced basal tear secretion and attenuated corneal epithelial injury in both murine and rat dry eye models. Mechanistic investigations revealed that QP-E treatment markedly inhibited VEGF-C secretion from classically activated (M1) macrophages, suppressed phosphorylation-dependent activation of the VEGF-C/VEGFR-3 signaling axis, and consequently impaired lymphatic endothelial cell migration and in vitro tube formation. These correlative findings indicate that QP-E may partially alleviate DED by suppressing lymphangiogenesis; however, direct causal evidence—such as genetic ablation of VEGF-C or pharmacological inhibition of VEGFR-3—was not established in the present study. Collectively, our data yield a testable mechanistic hypothesis and propose a novel therapeutic strategy targeting lymphatic remodeling for DED intervention.