Discovery of a highly selective VEGFR2 kinase inhibitor CHMFL-VEGFR2-002 as a novel anti-angiogenesis agent

Angiogenesis is an essential process in tumor growth, invasion and metastasis. VEGF receptor 2 (VEGFR2) inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment. However, most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration. Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view. Here we report the discovery and characterization of a novel VEGFR2 inhibitor (CHMFL-VEGFR2-002), which exhibited high selectivity among structurally closed kinases including PDGFRs, FGFRs, CSF1R, etc. CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay (IC = 66 nmol/L) and VEGFR2 autophosphorylation in cells (ECs ∼100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells (GI = 150 nmol/L). In addition, CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy and exhibited good PK (pharmacokinetics) profile with bioavailability over 49% and anti-angiogenesis efficacy in both zebrafish and mouse models without apparent toxicity. These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.

Efficacy of conversion therapy on future liver remnant hypertrophy for initially unresectable colorectal liver metastases: a review of current status and perspectives / 中华肝胆外科杂志

Surgical resection is the only effectively curative option for patients with colorectal liver metastases (CRLM).However,fewer than 20％ of those patients are deemed eligible for surgery when they were initially diagnosed.Conversion therapy,mainly used by chemotherapy,increases the opportunities of surgical treatment for patients with initially unresectable CRLM.Notably,sufficient future liver remnant (FLR)is a key factor for liver resection.The deficiency of FLR could lead to serious complications including postoperative liver failure.Surgical methods,represented by portal vein embolization (PVE),portal vein ligation (PVL) and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS),could increase FLR and subsequently further increase the surgical security for CRLM patients.Most CRLM patients accept systemic chemotherapy before surgery.With extensive research has revealed the chemotherapy-induced liver injury,more attention has been shifted to explore the influence of different chemotherapy regimens,chemotherapy cycles and timing of surgery on the volume of FLR.With this review,we overview the research status of conversion therapy for initial unresectable CELM and the influence of chemotherapy on the volume of FLR.