Liang Chris, Yuan Xiaobin, Shen Zhilin, Wang Yang, Ding Lieming
Betta Pharmaceuticals Co., Ltd., No. 355 Xingzhong Road, Yuhang District, Hangzhou, China.
Mol Ther Oncolytics. 2022 Jan 10;24:577-584. doi: 10.1016/j.omto.2022.01.001. eCollection 2022 Mar 17.
Vorolanib (CM082) is a multi-targeted tyrosine kinase receptor inhibitor with a short half-life and limited tissue accumulation that has been shown to reduce choroidal neovascularization in rats. In this preclinical study, vorolanib demonstrated competitive binding and inhibitory activities with KDR, PDGFRβ, FLT3, and C-Kit, and inhibited RET and AMPKα1 more weakly than sunitinib, indicating more stringent kinase selectivity. Vorolanib inhibited vascular endothelial growth factor (VEGF)-induced proliferation of human umbilical vein endothelial cells (HUVECs) and HUVEC tube formation . In mouse xenograft models, vorolanib inhibited tumor growth of MV-4-11, A549, 786-O, HT-29, BxPC-3, and A375 cells in a dose-dependent fashion. Complete tumor regression was achieved in the MV-4-11 xenograft model. No significant toxicities were observed in vorolanib groups, whereas a significant negative impact on body weights was observed in the sunitinib group at a dose of 40 mg/kg qd. Overall, vorolanib is a novel multi-kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity that is potentially less toxic than other similar kinase inhibitors.
沃罗替尼（CM082）是一种多靶点酪氨酸激酶受体抑制剂，半衰期短，组织蓄积有限，已被证明可减少大鼠脉络膜新生血管形成。在这项临床前研究中，沃罗替尼对KDR、PDGFRβ、FLT3和C-Kit表现出竞争性结合和抑制活性，对RET和AMPKα1的抑制作用比舒尼替尼弱，表明其激酶选择性更强。沃罗替尼抑制血管内皮生长因子（VEGF）诱导的人脐静脉内皮细胞（HUVECs）增殖和HUVEC管形成。在小鼠异种移植模型中，沃罗替尼以剂量依赖性方式抑制MV-4-11、A549、786-O、HT-29、BxPC-3和A375细胞的肿瘤生长。在MV-4-11异种移植模型中实现了肿瘤完全消退。沃罗替尼组未观察到明显毒性，而舒尼替尼组在剂量为40mg/kg每日一次时观察到对体重有显著负面影响。总体而言，沃罗替尼是一种新型多激酶受体抑制剂，具有强大的临床前抗血管生成和抗肿瘤活性，其毒性可能低于其他类似激酶抑制剂。
