Targeting the Ang2/Tie2 Axis with Tanshinone IIA Elicits Vascular Normalization in Ischemic Injury and Colon Cancer.

Pathological angiogenesis, as exhibited by aberrant vascular structure and function, has been well deemed to be a hallmark of cancer and various ischemic diseases. Therefore, strategies to normalize vasculature are of potential therapeutic interest in these diseases. Recently, identifying bioactive compounds from medicinal plant extracts to reverse abnormal vasculature has been gaining increasing attention. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza, has been shown to play significant roles in improving blood circulation and delaying tumor progression. However, the underlying mechanisms responsible for the therapeutic effects of Tan IIA are not fully understood. Herein, we established animal models of HT-29 human colon cancer xenograft and hind limb ischemia to investigate the role of Tan IIA in regulating abnormal vasculature. Interestingly, our results demonstrated that Tan IIA could significantly promote the blood flow, alleviate the hypoxia, improve the muscle quality, and ameliorate the pathological damage after ischemic insult. Meanwhile, we also revealed that Tan IIA promoted the integrity of vascular structure, reduced vascular leakage, and attenuated the hypoxia in HT-29 tumors. Moreover, the circulating angiopoietin 2 (Ang2), which is extremely high in these two pathological states, was substantially depleted in the presence of Tan IIA. Also, the activation of Tie2 was potentiated by Tan IIA, resulting in decreased vascular permeability and elevated vascular integrity. Mechanistically, we uncovered that Tan IIA maintained vascular stability by targeting the Ang2-Tie2-AKT-MLCK cascade. Collectively, our data suggest that Tan IIA normalizes vessels in tumors and ischemic injury via regulating the Ang2/Tie2 signaling pathway.

Novel TIE-2 inhibitor BAY-826 displays in vivo efficacy in experimental syngeneic murine glioma models.

Targeting the vascular endothelial growth factor signaling axis in glioblastoma inevitably leads to tumor recurrence and a more aggressive phenotype. Therefore, other angiogenic pathways, like the angiopoietin/tunica interna endothelial cell kinase (TIE) signaling axis, have become additional targets for therapeutic intervention. Here, we explored whether targeting the receptor tyrosine kinase TIE-2 using a novel, highly potent, orally available small molecule TIE-2 inhibitor (BAY-826) improves tumor control in syngeneic mouse glioma models. BAY-826 inhibits TIE-2 phosphorylation in vitro and in vivo as demonstrated by suppression of Angiopoietin-1- or Na3 VO4 -induced TIE-2 phosphorylation in glioma cells or extracts of lungs from BAY-826-treated mice. There was a trend toward prolonged survival upon single-agent treatment in two of four models (SMA-497 and SMA-540) and there was a significant survival benefit in one model (SMA-560). Co-treatment with BAY-826 and irradiation was ineffective in one model (SMA-497), but provided synergistic prolongation of survival in another (SMA-560). Decreased vessel densities and increased leukocyte infiltration were observed, but might be independent processes as the effect was also observed in single treatment modalities. These data demonstrate that TIE-2 inhibition may improve tumor response to treatment in highly vascularized tumors such as glioblastoma.

In Silico Exploration for Novel Type-I Inhibitors of Tie-2/TEK: The Performance of Different Selection Strategy in Selecting Virtual Screening Candidates.

The receptor tyrosine kinase Tie-2 is involved in vessel remodeling and maturation, and has been regarded as a potential target for the treatment of various solid tumors. The absence of novel, potent and selective inhibitors severely hampers the understanding of the therapeutic potential of Tie-2. In the present work, we describe the discovery of novel type-I inhibitors of Tie-2 by structure-based virtual screening. Preliminary SAR was also performed based on one active compound, and several novel inhibitors with low micro-molar affinity were discovered. To directly compare the efficiency between different filtering strategies in selecting VS candidates, two methods were separately carried out to screen the same chemical library, and the selected VS candidates were then experimentally assessed by in vitro enzymatic assays. The results demonstrate that the hit rate is improved when stricter drug-likeness criteria and less number of molecules for clustering analysis are used, and meanwhile, the molecular diversity of the compounds still maintains. As a case study of TIE-2, the information presented in this work underscores the importance of selecting an appropriate selection strategy in VS campaign, and the novel inhibitors identified and the detailed binding modes of action provide a starting point for further hit-to-lead optimization process.

Antiangiogenic therapy in oncology: current status and future directions.

Angiogenesis, the formation of new blood vessels from pre-existing vessels, has been validated as a target in several tumour types through randomised trials, incorporating vascular endothelial growth factor (VEGF) pathway inhibitors into the therapeutic armoury. Although some tumours such as renal cell carcinoma, ovarian and cervical cancers, and pancreatic neuroendocrine tumours are sensitive to these drugs, others such as prostate cancer, pancreatic adenocarcinoma, and melanoma are resistant. Even when drugs have yielded significant results, improvements in progression-free survival, and, in some cases, overall survival, are modest. Thus, a crucial issue in development of these drugs is the search for predictive biomarkers-tests that predict which patients will, and will not, benefit before initiation of therapy. Development of biomarkers is important because of the need to balance efficacy, toxicity, and cost. Novel combinations of these drugs with other antiangiogenics or other classes of drugs are being developed, and the appreciation that these drugs have immunomodulatory and other modes of action will lead to combination regimens that capitalise on these newly understood mechanisms.

Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent.

A substantial body of evidence supports the utility of antiangiogenesis inhibitors as a strategy to block or attenuate tumor-induced angiogenesis and inhibition of primary and metastatic tumor growth in a variety of solid and hematopoietic tumors. Given the requirement of tumors for different cytokine and growth factors at distinct stages of their growth and dissemination, optimal antiangiogenic therapy necessitates inhibition of multiple, complementary, and nonredundant angiogenic targets. 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (11b, CEP-11981) is a potent orally active inhibitor of multiple targets (TIE-2, VEGF-R1, 2, and 3, and FGF-R1) having essential and nonredundant roles in tumor angiogenesis and vascular maintenance. Outlined in this article are the design strategy, synthesis, and biochemical and pharmacological profile for 11b, which completed Phase I clinical assessing safety and pharmacokinetics allowing for the initiation of proof of concept studies.

Tie2 in tumor endothelial signaling and survival: implications for antiangiogenic therapy.

Signaling through the Tie2 receptor on endothelial cells has been shown to play an important role in normal and pathologic vascular development. We generated K1735 murine melanoma tumor cells that inducibly express soluble Tie2 receptor (Tie2Ex) to study the effects of inhibiting Tie2 signaling on tumor vasculature. Tie2Ex induction rapidly decreased AKT activation but not extracellular signal-regulated kinase (ERK) activation in tumor endothelial cells as detected by immunostaining. This was accompanied by an increase in endothelial cell TUNEL staining but no change in Ki-67 expression. Together with a decrease in the percentage of perfused vessels, this suggested that tumor vessel regression and impaired vascular function rather than angiogenesis inhibition was responsible for the delay in tumor growth following Tie2Ex treatment. However, Tie2Ex failed to inhibit the growth of larger, more established K1735 tumors. These tumors were additionally treated with sorafenib, a multikinase inhibitor that inhibits tumor endothelial cell ERK activation but not AKT activation. Combining Tie2Ex and sorafenib decreased both endothelial cell AKT and ERK activation, decreased endothelial cell survival and proliferation, and significantly inhibited growth of the more established tumors. These studies indicate that activity of specific signaling pathways and prosurvival effects are brought about by Tie2 activation in tumor endothelial cells, and knowledge of the effects of Tie2 inhibition can lead to development of more effective therapeutic regimens for inhibiting tumor neovascularization.

Angiogenesis inhibition as a therapeutic approach for inflammatory synovitis.

Angiogenesis inhibition, long studied in the treatment of malignancies, has begun to emerge as a potential therapeutic approach in managing inflammatory arthritis, particularly rheumatoid arthritis. The growth of new vessels is required for the development of the rheumatoid pannus, which then leads to extensive synovial inflammation and joint destruction. Vascular endothelial growth factor is the best studied mediator of angiogenesis, and several therapies have been developed that specifically target this molecule. Several other angiogenesis mediators, such as the angiopoietin-TIE system, hypoxia inducible factor and integrin alpha(V)beta(3), as well as naturally occurring inhibitors of angiogenesis, are also being investigated as potential therapeutic targets. Additionally, there are a number of drugs, including paclitaxel, 2-methoxyestradiol and fumagillin analogs, that might have a role in inhibiting angiogenesis and, thus, in treating proliferative synovitis.

Orally active 4-amino-5-diarylurea-furo[2,3-d]pyrimidine derivatives as anti-angiogenic agent inhibiting VEGFR2 and Tie-2.

During our effort to develop dual VEGFR2 and Tie-2 inhibitors as anti-angiogenic agents for cancer therapy, we discovered 4-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)- aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine (8a) possessing strong inhibitory activity at both the enzyme and cellular level against VEGFR2 and Tie-2. Compound 8a demonstrated high pharmacokinetic exposure through oral administration, and showed marked tumor growth inhibition and anti-angiogenic activity in mouse HT-29 xenograft model via once-daily oral administration.