J Cancer 2017; 8(14):2774-2784. doi:10.7150/jca.18731 This issue

Research Paper

CT-721, a Potent Bcr-Abl Inhibitor, Exhibits Excellent In Vitro and In Vivo Efficacy in the Treatment of Chronic Myeloid Leukemia

Yinghui Sun1, Na Zhao1, Huan Wang1, Qiong Wu1, Yunqi Han1, Qichao Liu1, Mangang Wu1, Yuliang Liu2, Fansheng Kong3, He Wang3, Ying Sun3, Deguang Sun2, Lutao Jing2, Guojing Tang2, Yuandong Hu2, Dengming Xiao2, Hong Luo3, Yongxin Han2, Yong Peng1✉

1. Department of Biology, Centaurus BioPharma Co., Ltd.;
2. Department of Medical Chemistry, Centaurus BioPharma Co., Ltd.;
3. Department of DMPK, Centaurus BioPharma Co., Ltd.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Sun Y, Zhao N, Wang H, Wu Q, Han Y, Liu Q, Wu M, Liu Y, Kong F, Wang H, Sun Y, Sun D, Jing L, Tang G, Hu Y, Xiao D, Luo H, Han Y, Peng Y. CT-721, a Potent Bcr-Abl Inhibitor, Exhibits Excellent In Vitro and In Vivo Efficacy in the Treatment of Chronic Myeloid Leukemia. J Cancer 2017; 8(14):2774-2784. doi:10.7150/jca.18731. Available from https://www.jcancer.org/v08p2774.htm

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Kinase inhibitors that target Bcr-Abl are highly effective in the treatment of chronic myeloid leukemia (CML). However, these inhibitors are often invalidated due to the drug resistance. Therefore, the discovery and development of novel Bcr-Abl inhibitors is required to overwhelm the drug resistance in the treatment of CML resistant to the currently used first-line Bcr-Abl inhibitors. Herein we have described a newly developed Bcr-Abl inhibitor CT-721, which displayed potent inhibitory effects on wild-type and T315I mutant Bcr-Abl. It functioned as a typically ATP-competitive inhibitor, superior to other existing Bcr-Abl inhibitors. CT-721 also demonstrated time-dependent inhibition of Bcr-Abl activation and the resultant downstream signaling transduction pathways in Bcr-Abl positive cells. Furthermore, CT-721 induced cell apoptosis and cell cycle arrest, and efficaciously inhibited tumor growth in Bcr-Abl-expressed K562 and KU812 xenograft models in a mechanism-based manner. Further PK/PD studies revealed a positive in vivo correlation between the compound concentration and inhibition of Bcr-Abl activity. Taken together, CT-721 is a potent and time-dependent Bcr-Abl kinase inhibitor, and has shown strong in vitro and in vivo anti-CML activities with a favorable pharmacokinetic profile, differentiating it from other Bcr-Abl kinase inhibitors already approved and current in development for the treatment of CML.

Keywords: CT-721, Bcr-Abl, anti-tumor, leukemia.