Development of Organometallic Protein Kinase Inhibitors with Anticancer Activity

具有抗癌活性的有机金属蛋白激酶抑制剂的开发

• 批准号: 8378454
• 负责人: ERIC MEGGERS
• 金额: $ 57.58万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8378454
• 关键词: Active Sites; Amides; Antineoplastic Agents; Apoptosis; BRAF gene; Back; Benzene; Binding; Biological; Biological Factors; Cancer cell line; Cell Line; Chemicals; Collaborations; Complement; Complex; Data; Development; Economics; Enzymes; Family; Fluorine; Genes; Glycogen Synthase Kinase 3; Goals; Human; Imides; In Vitro; Individual; Laboratories; Lead; Lesion; Ligands; Malignant Neoplasms; Melanoma Cell; Metals; Methodology; Modification; Molecular; Mutation; Nitrogen; Organometallic Compounds; Patients; Phosphotransferases; Play; Property; Protein Kinase; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Protocols documentation; Role; Ruthenium; Screening procedure; Shapes; Specificity; Structure; Structure-Activity Relationship; anticancer activity; base; combinatorial chemistry; design; feeding; human disease; improved; in vitro testing; in vivo; inhibitor/antagonist; kinase inhibitor; melanoma; mutant; new therapeutic target; next generation; novel; novel strategies; protein kinase inhibitor; pyridine; research study; scaffold; small molecule; therapeutic target

Mutations and dysregulation of protein kinases play causal roles in many human diseases, making kinases an important target for the development of pharmacological inhibitors. However, protein kinases are amongst the largest enzyme families with more than 500 putative protein kinase genes. As a consequence, the identification of inhibitors specific for individual protein kinases represents a significant and still unsolved challenge. Our group recently introduced a new concept of designing protein kinase inhibitors from organometallic scaffolds. These organometallic compounds display defined "natural product-like" shapes which has been demonstrated that it can lead to picomolar protein kinase inhibitors with excellent selectivities. In these organometallic compounds, the metal serves as a template for organizing the threedimensional structure of the small molecule, permitting a diversity of structural motifs and shapes that are complementary to the shape of enzyme active sites and are accessible through economic convergent synthesis. It is our goal to apply this powerful synthetic methodology to the development of inhibitors for kinases which are implicated as important therapeutic targets for the treatment of melanoma. Specifically, we are seeking inhibitors for the protein kinases BRAF, BRAFV600E, PI3Ka, and GSK-3|3. The rationale for selecting BRAF and PISKa is based on extensive biological data on their constitutive activation in melanoma cells both in cultured cell lines and in patients' lesions. GSK-Sp has emerged as an new therapeutic target in melanoma through direct pharmacological activation of p53. The inhibitors will be developed from a ruthenium-pyridocarbazole scaffold which, in preliminary results, yielded already nanomolar lead structures with promising selectivity profiles. Improved inhibitors for these kinases will be obtained by modifying the ligand sphere around the ruthenium and by functionalizing the pyridocarbazole moiety. To reach this goal we will use a combination of synthetic structure-activity relationships, combinatorial chemistry, and rational design. The synthetic approach is complemented by a structure-based design for BRAF, BRAFV600E, PISKa (Project 3) and GSK-3|3 (Project 4). First cocrystal structures of ruthenium inhibitors with PISKa and GSK-Sp have already been solved. We expect to obtain highly potent and selective ruthenium inhibitors for BRAF, BRAFV600E, PISKa, and GSK-3|3, which will be used for in vitro and in vivo studies in collaboration with the groups of M. Herlyn (Project 1) and D. Herlyn (Project 2).

蛋白激酶的突变和失调在许多人类疾病中起因果作用，使激酶 药理学抑制剂开发的重要目标。但是，蛋白激酶是 拥有500多个推定蛋白激酶基因的最大酶家族。结果， 鉴定特定于单个蛋白激酶的抑制剂代表着一个显着且仍未解决的抑制剂 挑战。我们的小组最近引入了一个新的概念，该概念是设计蛋白激酶抑制剂的 有机金属脚手架。这些有机金属化合物显示了定义的“天然产品”形状 已经证明它可以导致具有优异的皮摩尔蛋白激酶抑制剂 选择性。在这些有机金属化合物中，金属用作组织三维的模板 小分子的结构，允许多种结构基序和形状 互补地与酶活性站点的形状相辅相成，并可以通过经济融合来访问 合成。 我们的目标是将这种强大的合成方法论用于开发激酶的抑制剂 被认为是用于治疗黑色素瘤的重要治疗靶标。具体来说，我们正在寻找 蛋白激酶BRAF，BRAFV600E，PI3KA和GSK-3 | 3的抑制剂。选择BRAF的理由 Piska基于有关其在黑色素瘤细胞中构成激活的广泛生物学数据，均基于 培养的细胞系和患者病变。 GSK-SP已成为黑色素瘤的新治疗靶点 通过p53的直接药理激活。 这些抑制剂将是由氟吡唑巴唑支架开发的，在初步结果中， 产生的已经具有有希望的选择性曲线的纳摩尔铅结构。改善了这些抑制剂 激酶将通过修饰偶氮周围的配体球并通过功能化来获得激酶 吡二吡唑部分。为了实现这一目标，我们将结合合成结构活性 关系，组合化学和理性设计。合成方法与 BRAF，BRAFV600E，PISKA（项目3）和GSK-3 | 3（项目4）的基于结构的设计。第一个共晶 Piska和GSK-SP的唯一抑制剂的结构已经解决。我们希望获得 BRAF，BRAFV600E，PISKA和GSK-3 | 3的高度有效和选择性的唯一抑制剂，这将是 与M. Herlyn（项目1）和D. Herlyn合作，用于体外和体内研究 （项目2）。