Kinase insert domain protein receptor

Overview

Kinase insert domain protein receptor, more commonly known as KDR or VEGFR-2, is a receptor tyrosine kinase that serves as a major signaling receptor for vascular endothelial growth factor A (VEGFA). It is a central mediator of angiogenesis, endothelial cell proliferation, migration, and tube formation, and therefore plays a key role in vascular development and in the vascular remodeling that supports tumor growth and tissue repair.

In biomedical research, KDR is frequently studied as a therapeutic target in cancer, ischemic disease, and regenerative medicine. Because VEGF-A/VEGFR-2 signaling can be upregulated in tumors and in pro-angiogenic repair settings, KDR is often examined alongside related pathways and markers such as VEGFA, MAPK1, focal adhesion kinase, and JAK2/STAT3 signaling pathway components. Its inhibition is a common strategy in anti-angiogenic drug discovery, while its activation or normalization is explored in tissue regeneration and vascular repair.

Focus of Latest Publications

Recent publications have continued to examine Kinase insert domain protein receptor (KDR/VEGFR-2) primarily as an anti-angiogenic cancer target. Several studies focused on the design, synthesis, and biological evaluation of small-molecule VEGFR-2 inhibitors, including pyrazole-based, quinazoline-based, indolin-2-one, chalcone, and oxadiazole-containing scaffolds. These reports used a combination of in vitro cytotoxicity assays, enzyme inhibition assays, docking studies, and, in some cases, molecular dynamics simulations and ADMET profiling to assess target engagement and drug-likeness.

Across these studies, KDR was linked to anticancer activity in breast cancer, gastric cancer, lung cancer, hepatocellular carcinoma, and broader NCI-60 screening panels. One machine-learning and network pharmacology study of Schisandrin A in triple-negative breast cancer identified KDR among four prognosis-related core targets, although the strongest docking and experimental emphasis in that work was on other targets. In another in silico study of Pinellia ternata phytochemicals, KDR emerged as one of the core lung cancer-related targets, with baicalein predicted to bind KDR along with PTK2 and JAK2, supporting a proposed multi-target anti-angiogenic mechanism.

Experimental studies directly targeting KDR reported several promising lead compounds. A methoxyquinazoline sulfonamide derivative, compound 9a, showed strong VEGFR-2 inhibition, reduced HepG-2 cell migration, and was associated with decreased Akt phosphorylation, apoptosis, and G2/M arrest. Quinazolinone-based dual VEGFR-2/HDAC inhibitors also yielded a lead compound, 7d, with potent VEGFR-2 inhibition and strong anticancer activity. Similarly, piperazine-bridged indolin-2-one derivatives produced multiple VEGFR-2 inhibitors with selective cytotoxicity in breast cancer cells, and compound 10 induced G0/G1 arrest, apoptosis, and increased ROS generation.

Other publications reinforced KDR’s relevance in multi-target anticancer design. Chalcone-paracetamol hybrids identified compound 9 as a multi-target agent with significant VEGFR-2 inhibition alongside EGFR, COX-2, and tubulin-related activity. Pyrazole-oxadiazole-chalcone/oxime hybrids were also developed as dual EGFR/VEGFR-2 inhibitors, with compound 11b showing the highest potency against VEGFR-2 and inducing G2/M arrest and apoptosis. In a gastric cancer preclinical study, PB101 was evaluated as a VEGFR-1 decoy receptor intended to broaden anti-angiogenic blockade beyond VEGFR-2-related escape pathways involving VEGF-A, VEGF-B, and PlGF. Overall, these recent publications position KDR as a recurring focus in anti-angiogenic and anticancer drug discovery, especially in combination with apoptosis, cell-cycle arrest, and pathway modulation involving Akt1 and related signaling.

Key Publications

Jun Integrated Network Pharmacology and Machine Learning to Reveal the Mechanisms of Schisandrin A Against Triple-Negative Breast Cancer. (Journal of cellular and molecular medicine, 2026, PMID 42220063): "Utilizing the random forest survival algorithm, four prognosis-related core targets (GSK3B, IDO1, KDR, PKM) were identified from the METABRIC database, and the model's predictive performance was validated using the GSE58812 dataset."
May Applying artificial intelligence and machine learning framework for de novo design of pyrazole-based VEGFR-2 inhibitors. (Journal of molecular graphics & modelling, 2026, PMID 42208487): "VEGFR-2 is an important target for oncological interventions due to its key role in angiogenesis, a biological process vital for tumour expansion and metastasis."
May In-silico prediction of multi‑target mechanisms of Pinellia ternata phytochemicals in lung cancer: Evidence from a graph‑attention‑guided virtual screening and multi‑scale simulations. (PloS one, 2026, PMID 42149884): "the potential targets of Pinellia ternata highly overlap with lung cancer pathological genes, with FGFR4, CDK2, JAK2, KDR, PAK4, PTK2 and PDGFRA being the core."
May Therapeutic Efficacy of PB101 and Chemotherapy Combination in Preclinical Gastric Cancer Models. (Anticancer research, 2026, PMID 42049328): "Although anti-angiogenic therapies have yielded therapeutic benefit in GC, their efficacy is limited, as current vascular endothelial growth factor-A (VEGF-A) and VEGF receptor-2 (VEGFR-2) targeted therapies eventually fail due to compensatory pathways involving VEGF-B and placental growth factor (PlGF)."
Mar Novel methoxyquinazoline sulfonamide derivatives as angiogenesis inhibitors and radiosensitizers. (European journal of medicinal chemistry, 2026, PMID 41936795): "Compound 9a displayed strong inhibitory activity against VEGFR-2, with an IC50 value of 0.23 ± 0.03 μM, comparable to that of sorafenib."
Mar Design, synthesis, and in silico study of VEGFR-2 and HDAC dual acting quinazoline based molecules for anticancer evaluation. (Bioorganic chemistry, 2026, PMID 41903478): "Furthermore, it also showed a significant dual inhibition of VEGFR-2 and HDAC-2."
Jun Targeting VEGFR-2 with piperazine bridged indolin-2-one derivatives. (Bioorganic chemistry, 2026, PMID 41785707): "As a key mediator of tumor angiogenesis, VEGFR-2 has emerged as a promising therapeutic target for combating cancer."
May Nature-inspired chalcone-functionalized paracetamol derivatives as potential anticancer leads: synthesis, biological evaluation, apoptotic mechanisms, and in silico docking studies. (Bioorganic & medicinal chemistry letters, 2026, PMID 41621723): "Further biochemical analysis identified it (9) as a multi-target agent, with significant inhibitory activity against EGFR (0.62 ± 0.02 μM), VEGFR-2 (2.26 ± 0.01 μM), COX-2 (17.38 ± 0.13 μM), and tubulin polymerization (19.31 ± 0.29 μM)."
Jun Novel pyrazole-oxadiazole-chalcone/oxime hybrids as dual EGFR/VEGFR-2 inhibitors with promising anticancer potential: a comprehensive cytotoxicity evaluation, mechanistic insights and SAR analysis. (Molecular diversity, 2026, PMID 41563668): "A deeper biological assessment revealed that these hybrids act as dual inhibitors of EGFR and VEGFR-2, with compound 11b showing the highest potency (IC₅₀ = 26.38 nM and 114.17 nM, respectively)."