Rac GTPase-Specific Small Molecular Inhibitors

Rac GTPase 特异性小分子抑制剂

• 批准号: 8210890
• 负责人: YI ZHENG
• 金额: $ 24.2万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210890
• 关键词: Actins; Adhesions; Affinity; Animals; Biochemical; Biological; Blood; Blood Platelets; Bone Marrow; Bone Marrow Cells; Cell Adhesion Molecules; Cell physiology; Cells; Chemicals; Complex; Cytoskeletal Modeling; Distal; Drug Kinetics; Embryo; Erythrocytes; Event; Family; Fibroblasts; Funding; Future; Gene Targeting; Generations; Goals; Grant; Growth Factor; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Health; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Human; Imatinib; In Vitro; Kinetics; Lead; Malignant Neoplasms; Mediating; Microtubules; Modeling; Molecular; Mus; Myeloid Leukemia; Neoplasm Metastasis; Neurilemmoma; Organ; Pathologic; Pharmaceutical Chemistry; Phenotype; Physiological; Property; Protein Isoforms; Publications; Reaction; Regulation; Resolution; Role; Screening procedure; Signal Transduction; Silicon Dioxide; Specificity; Stream; Stress; Structure; Structure-Activity Relationship; T-Lymphocyte; Therapeutic; Therapeutic Effect; Toxic effect; Transducers; Translating; Ursidae Family; Validation; Work; Xenograft procedure; anti-cancer therapeutic; anticancer research; base; bcr-abl Fusion Proteins; cancer cell; cancer therapy; cell behavior; combinatorial; conventional therapy; cytokine; design; effective therapy; genetic regulatory protein; human disease; improved; in vivo; inhibitor/antagonist; innovation; insight; kinase inhibitor; leukemia; leukemic stem cell; member; migration; mouse model; novel; novel strategies; novel therapeutics; pre-clinical; progenitor; reconstitution; response; rho GTP-Binding Proteins; small molecule; stem; therapeutic target

DESCRIPTION (provided by applicant): The long-term objective of this project is to apply the mechanistic insights of the interaction between Rac GTPase of the Rho family and their regulatory proteins, the Dbl family guanine nucleotide exchange factors (GEFs) in particular, to the design of novel approaches to target deregulated Rac activities in human diseases such as cancer. The GEF-Rac signaling axis lies in the crossroads of many signaling events initiated by growth factors, cytokines, stress, and adhesion molecules. Their functional interaction leads to the activation of Rac and a variety of Rac-mediated physiological responses including actin and microtubule cytoskeletal reorganization, adhesion, migration, and proliferation. In the last funding period, we have studied the structure-function relationship of Rac1 in regard of its interaction with GEFs and effectors, and have succeeded in deriving structural and kinetic information of several functional interactions involving Rac1. Further, we have studied the role of Rac1 by a conditional gene targeting approach in mice to reveal several cell functions of Rac1 that could not have been discovered by conventional means. Last, we have discovered a first generation small molecule inhibitor, NSC23766, that is effective in targeting Rac in vitro and in vivo, and have utilized it to study a number of physiological and pathological functions of Rac GTPases ranging from hematopoietic stem cell mobilization, platelet regulation, to schwannoma phenotype reversion. In this proposal, we will (1) pursue structure-function based rational design and improvement of Rac-targeting small molecule inhibitors by screening and medicinal chemistry based on the newly resolved Rac1-NSC23766 crystal structure, and (2) apply the Rac-targeting small molecule inhibitors to leukemia stem cell mobilization from their bone marrow niche in a chronical myeloid leukemia mouse model. These mechanism-based studies of small molecule inhibitor design and pre-clinical validation in a novel pathologic context will not only provide an improved generation of Rac GTPase inhibitors for a wide range of usage in cancer research, but also will implicate an innovative avenue of application in mobilizing leukemia stem cells from their microenvironment, which can be utilized as an important regiment in combinatory therapy for effective eradication of cancer. PUBLIC HEALTH RELEVANCE: Rac GTPases have emerged as potential anti-cancer therapeutic targets by recent studies. The proposed work will pursue structure-based design of new chemical inhibitors of Rac GTPases by translating the mechanistic information obtained from the decade-long biochemical, structural, cell biological, and animal studies of Rac GTPases for anti-cancer therapy. Further, the proposed work will help establish a novel therapeutic concept that targeting Rac in leukemia stem cells could result in their mobilization from the niche. Our studies will raise a new possibility for future combinatory therapy in cancer research.

描述（由申请人提供）：该项目的长期目标是将Rho家族的Rac GTf 3与其调节蛋白（特别是Dbl家族鸟嘌呤核苷酸交换因子（GEF））之间相互作用的机理见解应用于设计靶向人类疾病（如癌症）中失调的Rac活性的新方法。GEF-Rac信号传导轴位于由生长因子、细胞因子、应激和粘附分子引发的许多信号传导事件的十字路口。它们的功能相互作用导致Rac的激活和多种Rac介导的生理反应，包括肌动蛋白和微管细胞骨架重组、粘附、迁移和增殖。在上一个资助期内，我们研究了Rac 1与GEFs和效应子相互作用的结构-功能关系，并成功地推导出涉及Rac 1的几种功能相互作用的结构和动力学信息。此外，我们已经研究了Rac 1的作用，在小鼠中的条件基因靶向方法，揭示了Rac 1的几个细胞功能，不能被发现通过常规手段。最后，我们发现了第一代小分子抑制剂NSC 23766，其在体外和体内有效靶向Rac，并利用其研究了Rac GTP酶的许多生理和病理功能，从造血干细胞动员、血小板调节到神经鞘瘤表型逆转。在该提案中，我们将（1）通过基于新解析的Rac 1-NSC 23766晶体结构的筛选和药物化学，寻求基于结构-功能的Rac靶向小分子抑制剂的合理设计和改进，以及（2）将Rac靶向小分子抑制剂应用于慢性髓性白血病小鼠模型中白血病干细胞从骨髓小生境的动员。这些基于机制的小分子抑制剂设计研究和在新的病理学背景下的临床前验证不仅将为癌症研究中的广泛用途提供改进的Rac GT3抑制剂一代，而且还将涉及从其微环境中动员白血病干细胞的创新应用途径，其可用作有效根除癌症的组合疗法中的重要方案。公共卫生相关性：Rac GTP酶已成为最近研究的潜在抗癌治疗靶点。拟议的工作将通过翻译从长达十年的Rac GTP酶的生物化学，结构，细胞生物学和动物研究中获得的机制信息来追求基于结构的Rac GTP酶新化学抑制剂的设计。此外，拟议的工作将有助于建立一种新的治疗概念，即靶向白血病干细胞中的Rac可能导致它们从利基中动员出来。我们的研究将为未来癌症研究中的联合治疗提供新的可能性。