Developing Chemical Probes to Decipher Gankyrin Biology

开发化学探针来破译 Gankyrin 生物学

• 批准号: 10569046
• 负责人: Aaron Muth
• 金额: $ 16.4万
• 依托单位: ST. JOHN'S UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569046
• 关键词: 26S proteasome; A549; ATP phosphohydrolase; Adaptor Signaling Protein; Animal Model; Ankyrin Repeat; Area; Binding; Biochemical Pathway; Biological; Biological Assay; Biology; Breast; Calorimetry; Cancer Biology; Cancer cell line; Cell Migration Inhibition function; Cell Proliferation; Cells; Chemicals; Colorectal; Cyclin-Dependent Kinases; Data; Development; Disease; Double Minutes; Down-Regulation; Epithelium; Evaluation; Future; Goals; Hep3B; HepG2; Hepatoblastoma; Human; Human Biology; Inflammation; Interleukin-6; Left; Link; Longitudinal Studies; Lung; MAPK8 gene; MDA MB 231; Malignant Neoplasms; Membrane; Mesenchymal; Metabolic; Mus; Neoplasm Metastasis; Oncogenic; Oncoproteins; Ovarian; PSMD10 gene; Pancreas; Pathway interactions; Permeability; Play; Primary carcinoma of the liver cells; Proliferating; Proteasome Binding; Proteins; Retinoblastoma Protein; Role; STAT3 gene; Severity of illness; Signal Transduction; Stomach; TNF gene; TP53 gene; Therapeutic; Tumor Suppressor Proteins; Work; cancer cell; cancer therapy; cancer type; cell motility; design; experimental study; improved; in silico; in vivo; insight; interdisciplinary approach; interest; knock-down; migration; molecular modeling; multicatalytic endopeptidase complex; next generation; novel; overexpression; prevent; protein protein interaction; scaffold; small molecule; small molecule inhibitor; therapeutic target; tool

Abstract. Gankyrin is an oncoprotein overexpressed in numerous cancer types and appears to play key roles in regulating cell proliferation, cell migration and epithelial-mesenchymal transition. These roles are primarily due to gankyrin’s numerous protein-protein interactions. The importance of these protein-protein interactions has been demonstrated by either decreasing gankyrin expression levels or directly disrupting its protein-protein interactions, which has resulted in decreased cell proliferation, cell migration and epithelial-mesenchymal transition, as well as disease severity in animal models of numerous cancer types. Therefore, gankyrin has been identified as an intriguing protein in multiple cancer types. However, much of how gankyrin regulates cell proliferation, cell migration and epithelial-mesenchymal transition is poorly understood. The overall goal of this proposal is to further develop our gankyrin-targeting probes which can be utilized to decipher much of gankyrin’s biological role in regulating cancer cell proliferation, migration and epithelial-mesenchymal transition. Furthermore, these probes will help in validating gankyrin as a therapeutic target due to its diverse roles in multiple cancer types. In order to achieve this goal, we are seeking to improve the ability of the cjoc42 scaffold to bind gankyrin and increase efficacy in specific cell-based assays. This proposal will also seek to provide preliminary data about gankyrin’s role in cancer biology, but the primary focus will be to develop and validate our probes as useful in future experiments. Ultimately, this proposal will provide the chemical probes required to fully understand gankyrin’s biological roles which will directly impact therapeutic advancements in multiple cancer types.

抽象的。 Gankyrin是多种癌症类型过表达的癌蛋白，似乎起关键作用 在调节细胞增殖，细胞迁移和上皮间质转变时。这些角色是主要的 Gankyrin的众多蛋白质 - 蛋白质相互作用。这些蛋白质蛋白相互作用的重要性具有 通过降低甘氏蛋白的表达水平或直接破坏其蛋白质蛋白质来证明 相互作用，导致细胞增殖，细胞迁移和上皮间质的减少 多种癌症类型的动物模型中的过渡以及疾病的严重程度。因此，Gankyrin一直 在多种癌症类型中被鉴定为一种有趣的蛋白质。但是，甘吉林如何调节细胞 增殖，细胞迁移和上皮 - 间质转变知之甚少。总体目标 建议是进一步开发我们的甘氏素靶向探针，可以用来破译甘吉林的大部分 生物学在调节癌细胞增殖，迁移和上皮间质转变中的作用。 此外，这些问题将有助于验证Gankyrin作为治疗目标，因为其在 多种癌症类型。为了实现这一目标，我们正在寻求提高CJOC42脚手架的能力 结合甘氏蛋白并提高基于特定细胞的测定的效率。该建议还将寻求提供 有关Gankyrin在癌症生物学中作用的初步数据，但主要重点是开发和验证我们 在将来的实验中有用的问题。最终，该提案将提供完全所需的化学问题 了解Gankyrin的生物学作用，这将直接影响多种癌症的热进步 类型。

项目成果

Small-Molecule Gankyrin Inhibition as a Therapeutic Strategy for Breast and Lung Cancer.

• DOI: 10.1021/acs.jmedchem.2c00190
• 发表时间: 2022-07-14
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Kanabar D;Goyal M;Kane EI;Chavan T;Kabir A;Wang X;Shukla S;Almasri J;Goswami S;Osman G;Kokolis M;Spratt DE;Gupta V;Muth A
• 通讯作者: Muth A