文章：

用小分子激酶抑制剂靶向癌症

Targeting cancer with small molecule kinase inhibitors

原文发布日期：2009-01-01

DOI: 10.1038/nrc2559

类型: Review Article

开放获取: 否

要点：

1. Small-molecule kinase inhibitors are being intensively pursued as new anticancer therapeutics. To date, approximately 80 inhibitors have been advanced to some stage of clinical evaluation.
2. Understanding the structural basis of kinase inhibitor selectivity is crucial to the ultimate goal of developing selective inhibitors to target every member of the kinome. Most currently known kinase inhibitors target the ATP binding site with the kinase activation loop in the active (type 1) or inactive (type 2) conformation.
3. New kinase inhibitors are primarily developed with a combination of methods, including high-throughput screening using biochemical or cellular assays, analogue synthesis, structure-guided design and fragment-based assembly strategies.
4. The repertoire of kinases targeted by a given inhibitor can be determined by profiling its activity in binding and enzymatic assays against extensive panels of recombinant kinases, by profiling activity in cellular assays and by affinity approaches integrated with detection by mass spectrometry.
5. Kinase inhibitor resistance resulting from selection for mutant alleles or upregulation of alternative signalling pathways is a recurrent theme in the clinic. Strategies for developing multiple inhibitors targeting different kinase sites and for discovering synergistic inhibitor combinations are urgently needed.

要点翻译：

1. 小分子激酶抑制剂作为新型抗癌疗法正受到深入研究。目前约有80种抑制剂已进入不同阶段的临床评估。
2. 理解激酶抑制剂选择性的结构基础，对于实现针对激酶组每个成员开发选择性抑制剂的终极目标至关重要。目前已知的大多数激酶抑制剂以ATP结合位点为靶点，其作用时激酶活化环可处于活性（1型）或非活性（2型）构象。
3. 新型激酶抑制剂主要通过多种方法联合开发，包括采用生化或细胞检测的高通量筛选、类似物合成、结构导向设计以及基于片段的组装策略。
4. 特定抑制剂靶向的激酶谱系可通过多种方式确定：在重组激酶扩展组中进行结合活性和酶活性分析、通过细胞检测分析活性，以及结合质谱检测的亲和力研究方法。
5. 由突变等位基因选择或替代信号通路上调引起的激酶抑制剂耐药性，是临床治疗中反复出现的问题。当前亟需制定针对不同激酶位点的多重抑制剂开发策略，并探索协同作用的抑制剂组合方案。

英文摘要：

Deregulation of kinase activity has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. To date, 11 kinase inhibitors have received US Food and Drug Administration approval as cancer treatments, and there are considerable efforts to develop selective small molecule inhibitors for a host of other kinases that are implicated in cancer and other diseases. Herein we discuss the current challenges in the field, such as designing selective inhibitors and developing strategies to overcome resistance mutations. This Review provides a broad overview of some of the approaches currently used to discover and characterize new kinase inhibitors.

摘要翻译： 

激酶活性的失调已成为癌细胞逃避生长和存活正常生理约束的主要机制之一。迄今为止，已有11种激酶抑制剂获得美国食品药品监督管理局批准用于癌症治疗，同时人们正投入大量努力开发针对其他与癌症及其他疾病相关激酶的选择性小分子抑制剂。本文讨论了当前该领域面临的挑战，例如设计选择性抑制剂以及制定克服耐药性突变的策略。本综述广泛概述了目前用于发现和表征新激酶抑制剂的一些方法。

原文链接：

Targeting cancer with small molecule kinase inhibitors