Identification of GZD824 as an Orally Bioavailable Inhibitor That Targets Phosphorylated and Nonphosphorylated Breakpoint Cluster Region-Abelson (Bcr-Abl) Kinase and Overcomes Clinically Acquired Mutation-Induced Resistance against Imatinib
Identification of GZD824 as an Orally Bioavailable Inhibitor That Targets Phosphorylated and Nonphosphorylated Breakpoint Cluster Region-Abelson (Bcr-Abl) Kinase and Overcomes Clinically Acquired Mutation-Induced Resistance against Imatinib
复制标题
鉴定 GZD824 作为一种口服生物可利用抑制剂，靶向磷酸化和非磷酸化断点簇区域 - Abelson (Bcr-Abl) 激酶并克服临床获得性突变诱导的伊马替尼耐药性
DOI：
10.1021/jm301581y
复制
发表时间：
2013-02-14
影响因子：
7.3
通讯作者：
Ding, Ke
中科院分区：
文献类型：
--
作者：
Ren, Xiaomei;Pan, Xiaofen;Ding, Ke
Bcr-Abl（T315）I突变诱导的伊马替尼耐药仍然是慢性粒细胞白血病（CML）临床管理的主要挑战。在此，我们报告了GZD 824（10a）作为一种新型口服生物可利用的抑制剂，针对包括T315 I在内的广谱Bcr-Abl突变体。它与Bcr-Abl（WT）和Bcr-Abl（T315 I）紧密结合，Kd值分别为0.32和0.71 nM，并强烈抑制激酶功能，IC 50值为纳摩尔。该化合物有效抑制Bcr-Abl阳性K562和Ku 812人CML细胞的增殖，IC 50值分别为0.2和0.13 nM。它还显示出良好的口服生物利用度（48.7%），合理的半衰期（10.6小时），和有前途的体内抗肿瘤疗效。在Bcr-Abl（WT）或突变体驱动的小鼠异种移植肿瘤模型中，它诱导肿瘤消退，并显著改善了携带携带Bcr-Abl（T315 I）Ba/F3细胞的同种异体移植白血病模型小鼠的存活率。GZD 824代表了开发Bcr-Abl抑制剂以克服获得性伊马替尼耐药性的有希望的主要候选药物。
Bcr-Abl(T315)I mutation-induced imatinib resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Herein, we report GZD824 (10a) as a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. It tightly bound to Bcr-Abl(WT) and Bcr-Abl(T315I) with K-d values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC50 values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC50 values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl(WT) or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl(T315I). GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance.