葉嘉煒，趙立文，張倉，尤啟冬

（1. 中國藥科大學(xué)藥物化學(xué)教研室，江蘇 南京 210009；2. 南京圣和藥業(yè)有限公司，江蘇 南京 210038）

針對T315I突變的Bcr-Abl酪氨酸激酶抑制劑研究進展

葉嘉煒1,2，趙立文2，張倉2，尤啟冬1*

（1. 中國藥科大學(xué)藥物化學(xué)教研室，江蘇 南京 210009；2. 南京圣和藥業(yè)有限公司，江蘇 南京 210038）

BCR-ABL是一種由bcr基因和c-abl原癌基因融合產(chǎn)生的致癌基因。該基因表達的Bcr–Abl癌蛋白是慢性粒細胞白血病的病理學(xué)基礎(chǔ)。因此研發(fā)選擇性的Bcr–Abl酪氨酸激酶抑制劑成為治療慢性粒細胞白血病的一種有效策略。目前已有數(shù)個Bcr–Abl酪氨酸激酶抑制劑獲準(zhǔn)上市。然而，Abl激酶結(jié)構(gòu)域的突變或其他原因?qū)е履[瘤耐藥性的出現(xiàn)，其中T315I突變是最重要的突變之一，引發(fā)的耐藥性更是難以克服。重點介紹了針對T315I突變的Bcr–Abl酪氨酸激酶抑制劑的研究進展。

酪氨酸激酶；慢性粒細胞白血病；Bcr-Abl激酶抑制劑；耐藥性；天冬氨酸-苯丙氨酸-甘氨酸基序

費城（Ph）染色體是人類最普遍的異常染色體，它由染色體22和9之間的t（9；22）（q34；q11）易位形成[1]。這種易位形成2種雜交基因：Ph染色體上的bcr-abl和9q+上的abl-bcr。融合基因bcr-abl轉(zhuǎn)錄翻譯產(chǎn)生Bcr-Abl融合蛋白，該蛋白具有持續(xù)性激活酪氨酸激酶活性的作用[2]，這被看作是慢性期（CP）慢性粒細胞白血?。–ML）的主要病理機制[3]。Bcr-Abl的激酶結(jié)構(gòu)域（見圖1）包含2個柔性環(huán)：能夠結(jié)合ATP的P環(huán)（P-loop）和負責(zé)催化的A環(huán)（activation loop）。A環(huán)N端的天冬氨酸381-苯丙氨酸382-甘氨酸383（簡稱D381-F382-G383或DFG）基序高度保守。DFG的相對位置決定Abl的激酶活性：處于“DFG-in”構(gòu)象時Abl具有活性；而當(dāng)其處于“DFG-out”構(gòu)象時則無活性。

圖1 Bcr-Abl酪氨酸激酶結(jié)構(gòu)域示意圖

Bcr-Abl激酶被認為是治療CML的一個具有相當(dāng)吸引力的靶點，由此出現(xiàn)了大量Bcr-Abl酪氨酸激酶抑制劑

Abl in chronic myeloid leukemia and imatinib: insights from a

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Advances in Research on Bcr-Abl Tyrosine Kinase Inhibitors against T315I Mutation

YE Jiawei1,2, ZHAO Liwen2, ZHANG Cang2, YOU Qidong1
( 1. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; 2. Nanjin Sanhome Pharmaceutical Co., Ltd., Nanjing 210038, China )

BCR-ABL is an oncogene that arises from the fusion of the bcr gene and the c-abl proto-oncogene. The Bcr-Abl oncoprotein is believed to be the primary cause of chronic myelogenous leukemia (CML). Thus, the development of selective Bcr-Abl kinase inhibitors is an attractive strategy to treat CML. Several Bcr-Abl tyrosine kinase inhibitors (Bcr-Abl TKIs) have been approved recently. However, multiple drug resistance of tumor cells against the existing Bcr-Abl TKIs has emerged due to the mutations in the Abl kinase domain or other reasons. Among them the T315I mutation is the most diffcult one to be treated. The recent progress in research on Bcr-Abl TKIs against T315I mutation has been reviewed in this paper.

tyrosine kinase; chronic myelogenous leukemia; Bcr-Abl kinase inhibitor; drug resistance; DFG motif

R979.1

A

1001-5094(2014)05-0333-07

接受日期：2014-03-13

*通訊作者：尤啟冬，教授,中國藥學(xué)會藥物化學(xué)專業(yè)委員會副主任委員；

研究方向：抗腫瘤藥物研發(fā)；

Tel：025-83271351；E-mail：youqidong@gmail.com