Tivozanib (AV-951)|475108-18-0|安捷凯

Tivozanib (AV-951)

Tivozanib (AV-951; KRN951) 是一种有效的、选择性的、具有口服活性的 VEGFR 酪氨酸激酶抑制剂，对 VEGFR-1、VEGFR-2、VEGFR-3 的 IC50 分别为 0.21、0.16、0.24 nM。 Tivozanib 抑制肿瘤组织中的血管生成和血管通透性，并显示出抗肿瘤活性。 Tivozanib 具有研究转移性肾细胞癌（RCC）的潜力。

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Background

Tivozanib is an inhibitor of tyrosine kinase with IC50 value of 160 pmol/L against VEGFR-2 [1].

Tivozanib is a quinoline-urea derivative. As a 2nd generation TKI, it has picomolar potency against VEGFR-1, -2 and -3, and minimal c-kit inhibition. Among this, Tivozanib has demonstrated a VEGFR-2 potency 2 orders of magnitude greater than sunitinib, sorafenib or pazopanib and a lower relative extent of off-target inhibition [1]. Tivozanib also shows to inhibit phosphorylation of the kinases PDGFR? and C-KIT at nanomolar level in cellular assays [2].

Tivozanib has shown antitumor activity in RCC xenograft models in addition to several other solid tumor models leading to its evaluation in clinical testing. The safety and efficacy of Tivozanib has been evaluated in several Phase I and Phase II trials. To compare the front-line use of tivozanib to sorafenib, a pivotal randomized Phase III trial has also been reported [3].

参考文献:
[1] M.N. Fishman, S. Srinivas, R.J. Hauke, R.J. Amato, B. Esteves, M.M. Cotreau, A.L. Strahs, W.J. Slichenmyer, P. Bhargava, F.F. Kabbinavar. Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma. European Journal of Cancer. 2013(49):2841-2850.
[2] Viktor Grunwald, Axel Stuart Merseburger. The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors – Is there more to come? European Journal of Cancer. 2013(49):2504-2511.
[3] C Lance Cowey. Profile of tivozanib and its potential for the treatment of advanced renal cell carcinoma. Drug Design, Development and Therapy. 2013 (7): 519-527.

Protocol

Cell experiment [1]:

Cell lines

Human ovarian carcinoma cell lines, including A2780CP, OVCAR3 and SKOV3.

Preparation method

Soluble in DMSO >22.8mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

10μm, 48h

Applications

Combination of tivozanib with the EGFR(Epidermal Growth Factor Receptor)-directed therapies displayed synergistic activity on cell growth inhibition and induction of apoptosis, suggesting that anti-VEGFR(vascular endothelial growth factor receptor) -targeted approaches induced sensitisation to the EGFR-directed therapies.

Clinical experiment [2]:

Diseases models

Patients with renal cell carcinoma(RCC)

Dosage form

1.5 mg OD for 3 weeks, oral administration

Application

Tivozanib exhibit an inhibitory profile with high sensitivity for inhibition of VEGFR family members. Patients receiving tivozanib had a PFS(Progression free survival) of 12.7 months – the best PFS reported in a phase III trial with mRCC.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

参考文献:

[1]. Momeny M1, Sabourinejad Z2,3, et al, Anti-tumour activity of tivozanib, a pan-inhibitor of VEGF receptors, in therapy-resistant ovarian carcinoma cells. Sci Rep. 2017 Apr 6;7:45954. doi: 10.1038/srep45954.

[2]. Grünwald V1, Merseburger AS2. The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors – Is there more to come Eur J Cancer. 2013 Jul;49(11):2504-11. doi: 10.1016/j.ejca.2013.03.022. Epub 2013 Apr 16.

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Tivozanib (AV-951)

Tivozanib (AV-951)详情

Background

Protocol

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