Discovery of a Highly Selective VEGFR2 Kinase Inhibitor CHMFL-VEGFR2-002 as a Novel Anti-angiogenesis Agent

Publication date: Available online 18 October 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Zongru Jiang, Li Wang, Xuesong Liu, Cheng Chen, Beilei Wang, Wenliang Wang, Chen Hu, Kailin Yu, Ziping Qi, Qingwang Liu, Aoli Wang, Jing Liu, Guangchen Hong, Wenchao Wang, Qingsong LiuAbstractAngiogenesis 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 (IC50=66 nmol/L) and VEGFR2 autophosphorylation in cells (EC50s ∼100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells (GI50=150 nmol/L). In addition, CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy in vitro and exhibited good in vivo PK (pharmacokinetics) profile with bioavailability over 49% and anti-angiogenesis efficacy in both zeb...
Source: Acta Pharmaceutica Sinica B - Category: Cancer & Oncology Source Type: research

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Publication date: Available online 13 November 2019Source: Progress in Biophysics and Molecular BiologyAuthor(s): Kiel Hards, Cara Adolph, Liam K. Harold, Matthew B. McNeil, Chen-Yi Cheung, Adrian Jinich, Kyu Y. Rhee, Gregory M. CookAbstractCellular bioenergetics is an area showing promise for the development of new antimicrobials, antimalarials and cancer therapy. Enzymes involved in central carbon metabolism and energy generation are essential mediators of bacterial physiology, persistence and pathogenicity, lending themselves natural interest for drug discovery. In particular, succinate and malate are two major focal po...
Source: Progress in Biophysics and Molecular Biology - Category: Molecular Biology Source Type: research
Yicheng Ni Cancer remains a major cause of death globally. Given its relapsing and fatal features, curing cancer seems to be something hardly possible for the majority of patients. In view of the development in cancer therapies, this article summarizes currently available cancer therapeutics and cure potential by cancer type and stage at diagnosis, based on literature and database reviews. Currently common cancer therapeutics include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, treatment with curative intent by these methods are mainly eligible for patients with localized diseas...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
Chem. Commun., 2019, Accepted Manuscript DOI: 10.1039/C9CC07683B, Feature ArticleZhen Chen, Haoqiang Lai, Liyuan Hou, Tianfeng Chen Organo-seleno compounds (org-Se) have been widely used in antitumor, antivirus, antiinflammation, antioxidation and other biological fields. As such, they have made an important contribution in overcoming various kinds of diseases... The content of this RSS Feed (c) The Royal Society of Chemistry
Source: RSC - Chem. Commun. latest articles - Category: Chemistry Authors: Source Type: research
Catecholamines released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type, including myeloid-derived suppressor cells (MDSCs). Using in vitro systems, murine tumor models in wild-type and genetically modified (β2-AR–/–) mice, and adoptive transfer approaches, we found that the degree of β2-AR signaling significantly influences MDSC frequency and survival in tumors and other tissues. It also modulates their expression of immunosuppressive molecules such as arginase-I and PD-L1 and alters their ability to suppress the proliferation of T cells. The regulatory funct...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
Tumor-induced immunosuppression is a common obstacle for cancer treatment. Adrenergic signaling triggered by chronic stress participates in the creation of an immunosuppressive microenvironment by promoting myeloid-derived suppressor cell (MDSC) proliferation and activation. In this issue of the JCI, Mohammadpour et al. elegantly delve into the mechanisms underlying MDSC contribution to tumor development. They used in vitro and in vivo mouse models to demonstrate that chronic stress results in MDSC accumulation, survival, and immune-inhibitory activity. Of therapeutic relevance, the authors showed that propranolol, a commo...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
Cardio-oncology has developed as a new field due to the proliferation of novel cancer therapies that not only have improved outcomes for some types of cancer, but also may lead to various cardiovascular toxicities. Older therapies, such as anthracyclines, are associated with cardiomyopathy as a result of myocyte death at the time of treatment, followed by cardiac remodeling in the years following completion of therapy, and eventually lead to heart failure (HF). In 2019, data are limited on the prevention and treatment of cancer treatment –associated cardiomyopathy, with most interventions extrapolated from general HF...
Source: JAMA - Category: General Medicine Source Type: research
Tumor-induced angiogenesis has been a significant focus of anti-cancer therapies for several decades. The immature and “leaky” tumor vasculature leads to significant cancer cell intravasation, increasing the metastatic potential, while the disoriented and hypo-perfused tumor vessels hamper the anti-tumor efficacy of immune cells and prevent the efficient diffusion of chemotherapeutic drugs. Therefore, tumor vascular normalization has emerged as a new treatment goal, aiming to provide a mature tumor vasculature, with higher perfusion, decreased cancer cell extravasation, and higher efficacy for anti-cancer thera...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
This study evaluated health-related quality of life (HRQOL) using patient-reported outcomes in subjects with mucinous appendiceal neoplasms who underwent cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as part of a randomized trial comparing mitomycin with oxaliplatin.MethodsIn this prospective multicenter study, 121 mucinous appendiceal cancer patients, with evidence of peritoneal dissemination who underwent CRS, were randomized to receive mitomycin (divided 40  mg) or oxaliplatin (200 mg/m2) for HIPEC. The Functional Assessment of Cancer Therapy Neurotoxicity (FACT-G/NTX) ques...
Source: Annals of Surgical Oncology - Category: Cancer & Oncology Source Type: research
ConclusionElevated troponin levels predict LV dysfunction in patients receiving cancer therapy. Assessment of troponin levels may qualify as a screening test to identify patients who require referral to cardio ‐oncology units and benefit from preventive strategies. Further evidence is required for both biomarkers.
Source: European Journal of Heart Failure - Category: Cardiology Authors: Tags: Research Article Source Type: research
;o AQ Abstract CAR-T cell therapy emerged in the last years as a great promise to cancer treatment. Nowadays, there is a run to improve the breadth of its use, and thus, new chimeric antigen receptors (CAR) are being proposed. The antigen-binding counterpart of CAR is an antibody fragment, scFv (single chain variable fragment), that recognizes a membrane protein associated to a cancer cell. In this chapter, the use of human scFv phage display libraries as a source of new mAbs against surface antigen is discussed. Protocols focusing in the use of extracellular domains of surface protein in biotinylated format are p...
Source: Mol Biol Cell - Category: Molecular Biology Authors: Tags: Methods Mol Biol Source Type: research
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