Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Mol Cancer. 2018 Feb 19;17(1):48. doi: 10.1186/s12943-018-0804-2.
The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.
人类基因组编码了 538 种蛋白激酶，这些激酶将 ATP 中的γ-磷酸基团转移到丝氨酸、苏氨酸或酪氨酸残基上。这些激酶中有许多与人类癌症的发生和发展有关。近年来，小分子激酶抑制剂在治疗多种类型的癌症方面已被证明在临床治疗中取得了成功。重要的是，蛋白激酶是继 G 蛋白偶联受体之后第二个靶向药物靶点最多的药物靶点。自上世纪 80 年代初开发出第一种蛋白激酶抑制剂以来，已有 37 种激酶抑制剂获得 FDA 批准，用于治疗乳腺癌和肺癌等恶性肿瘤。此外，约有 150 种激酶靶向药物正在进行临床阶段试验，许多激酶特异性抑制剂处于药物开发的临床前阶段。然而，许多因素影响了这些分子的临床疗效。特定的肿瘤遗传学、肿瘤微环境、耐药性和药物基因组学决定了一种化合物在治疗特定癌症方面的有效性。本文综述了激酶靶向药物的发现和开发与肿瘤学的关系，并强调了激酶靶向癌症治疗的挑战和未来潜力。
