CAJ | 학술논문

蛋白激酶是细胞内信号转导通路网络的关键组成部分，调节细胞生长、分化、代谢及生存等重要生物学过程。激酶组(kinome)是指细胞或组织中所有激酶的总称。激酶组学（kinomics）是研究激酶组的学科，包括激酶的丰度、活性、底物特异性、磷酸化状态及氨基酸突变。目前人激酶组由568种基因编码组成，其中约50%激酶定位于疾病基因位点。由于基因扩增或突变引起的蛋白激酶活性失调与许多疾病的发生相关，包括炎症、糖尿病及各种肿瘤，因此，人激酶组被认为是药物靶点的潜在资源库。靶向激酶的小分子抑制剂已成功用于肿瘤治疗。化学蛋白质组技术是一种新的深入研究激酶组的方法，是将亲和富集与质谱技术相结合，在生理状态下研究激酶丰度及磷酸化水平。通常情况下，将一个或多个广谱小分子激酶抑制剂偶联于固相载体（如琼脂糖凝胶），亲和富集细胞或组织中的所有激酶，然后通过质谱鉴定或定量。该方法可用于激酶抑制剂药物或药物候选物的靶点专一性及耐药机制研究，为深入研究药物作用机制及寻找联合用药新靶点提供依据。对人激酶组及肿瘤激酶组无偏见、全景式分析能帮助发现更多新药靶点，以及激酶活性谱与肿瘤治疗的相关性，为个体化治疗提供依据。本文对人激酶组、激酶、激酶抑制剂与肿瘤的关系，基于化学蛋白质组的激酶组学研究进展及其在药物研究中的最新应用进行综述。
단백격매시세포내신호전도통로망락적관건조성부분，조절세포생장、분화、대사급생존등중요생물학과정。격매조(kinome)시지세포혹조직중소유격매적총칭。격매조학（kinomics）시연구격매조적학과，포괄격매적봉도、활성、저물특이성、린산화상태급안기산돌변。목전인격매조유568충기인편마조성，기중약50%격매정위우질병기인위점。유우기인확증혹돌변인기적단백격매활성실조여허다질병적발생상관，포괄염증、당뇨병급각충종류，인차，인격매조피인위시약물파점적잠재자원고。파향격매적소분자억제제이성공용우종류치료。화학단백질조기술시일충신적심입연구격매조적방법，시장친화부집여질보기술상결합，재생리상태하연구격매봉도급린산화수평。통상정황하，장일개혹다개엄보소분자격매억제제우련우고상재체（여경지당응효），친화부집세포혹조직중적소유격매，연후통과질보감정혹정량。해방법가용우격매억제제약물혹약물후선물적파점전일성급내약궤제연구，위심입연구약물작용궤제급심조연합용약신파점제공의거。대인격매조급종류격매조무편견、전경식분석능방조발현경다신약파점，이급격매활성보여종류치료적상관성，위개체화치료제공의거。본문대인격매조、격매、격매억제제여종류적관계，기우화학단백질조적격매조학연구진전급기재약물연구중적최신응용진행종술。
Protein kinases are key components of cell signaling networks and thereby regulate fundamental biological processes such as cellular growth, proliferation, metabolism and survival. Kinome refers to all kinases in cells or tissue and “kinomics”is the global analysis of kinome with respect to abundance, activity, substrate specificity, phosphorylation pattern and mutational status. Human kinome currently contains 568 members, nearly half of which can be mapped to disease loci and deregulation of kinase activity by gene amplifica-tion or mutations has been implicated in diseases such as inflammation, diabetes and cancer. Therefore, human kinome is being recognized as a potentially rich source of drug targets. Kinase inhibitors have been successfully used to treat many kinds of advanced cancers. Chemi-cal proteomics is emerging as a novel comprehensive kinome approach that combines an immobilized inhibitor affinity pull-down approach with mass spectrometry-based proteomics for kinase identification, quantification and phosphorylation analysis under physiological condi-tion. Commonly, one or multiple broad-spectrum kinase inhibitors are covalently immobilized on a biocompatible matrix such as sepharose to enrich all kinases in cells or tissue and then the kinases are identified and quantified by mass spectrometry analysis. It can be used to study the specificity of kinase inhibitor drug, drug candidate or drug resistance mechanism, which can help to understand the mechanism and find combinational drug target. Large-scale unbiased kinome and cancer kinome study will facilitate new drug target discovery and correlate tumor tissue kinome profiles with response to therapy and therefore may be used for future therapy selection in personalized medicine. In this paper, the human kinome, kinase, kinase inhibitor and cancer, chemical proteomics based kinome study progress and its applications in drug discovery are reviewed.