Development of novel selective Rac inhibitors for refractory leukemias

开发治疗难治性白血病的新型选择性 Rac 抑制剂

• 批准号: 9319224
• 负责人: DAVID A WILLIAMS
• 金额: $ 60.3万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-20 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319224
• 关键词: Acute leukemia; Affinity Chromatography; Alternative Splicing; Animal Model; Attenuated; Binding; Biochemical; Bioinformatics; Biology; Candidate Disease Gene; Cell Line; Cell model; Cell physiology; Cellular biology; Characteristics; Chronic Myeloid Leukemia; Code; Collaborations; Colon Carcinoma; Computer Simulation; Crystallography; Data; Development; Disease; Dose; Excretory function; Exhibits; Family; Genetic; Genetic Models; Germany; Guanosine Triphosphate Phosphohydrolases; Hematopoietic stem cells; Human; In Vitro; Laboratories; Lead; Lesion; Leukemic Cell; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mammalian Cell; Mediating; Metabolism; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Mutate; Mutation; Oncogenes; Output; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Play; Pre-Clinical Model; Property; Proteins; Refractory; Relapse; Role; Sampling; Series; Signal Pathway; Signal Transduction; Solid; Solid Neoplasm; Specificity; Techniques; Testing; Therapeutic; TimeLine; Validation; Work; Xenograft Model; absorption; analog; base; bcr-abl Fusion Proteins; cancer therapy; cell growth; cellular targeting; conventional therapy; drug discovery; experience; extracellular; high risk; improved; in vivo; inhibitor/antagonist; interest; knock-down; leukemia; malignant breast neoplasm; melanoma; new therapeutic target; novel; oncology; outcome forecast; preclinical development; programs; rac GTP-Binding Proteins; relapse risk; research clinical testing; response; rho GTP-Binding Proteins; screening; small hairpin RNA; small molecule inhibitor; therapeutic target; tool; virtual

Project summary/abstract Rac belongs to the family of Rho GTPases, proteins that regulate critical cellular functions by integrating extracellular signals and coordinating activation of downstream effectors. In several models of leukemia (BCR-ABL, MLL-rearranged and RAS-mutated leukemia), Rac is aberrantly activated and its genetic deletion can attenuate the transforming effect of driver oncogenes. Moreover, increased activation of Rac due to the expression of an alternative splicing version or to mutations in its coding sequence has been shown to play a critical role in the malignant progression of some solid tumors, including breast, lung and colon cancer as well as melanoma. Due to its biochemical properties, Rac has not been fully exploited as a therapeutic target in cancer. However, a tool compound (NSC 23766) that inhibits Rac activation at high concentration in mammalian cells has been previously developed and inhibits malignant transformation mediated by BCR-ABL in vitro and in vivo. In the present project, the Williams laboratory, a leader in Rho GTPase biology in hematopoietic stem cells, is partnering with Evotec (a medicinal chemistry company with deep expertise in drug discovery) to carry out orthogonal approaches to develop small molecule inhibitors of Rac for the treatment of refractory leukemias (in particular, MLL- rearranged and RAS-mutated). We propose the following approaches to identify new inhibitors and develop recently identified compounds into lead molecules: 1) Optimization of DW_0069, the lead compound previously identified by a virtual screening for Rac inhibitors. This compound inhibits Rac activation in vitro and in vivo, and is well tolerated in leukemia xenograft models. We have already identified several analogues with increased potency. In this project, we propose to further optimize this compound and to investigate its mechanism of action. 2) Expansion of a fragment-based drug discovery program for Rac inhibitors, and development of additional hits identified by a fragment-based NMR screen. Criteria for prioritization of compound development will involve extended SAR studies, good absorption, distribution, metabolism, and excretion- (ADME) properties, and activity in advanced cellular and animal models of RAS-mutated and MLL-rearranged leukemias. The project proposal includes a timeline for nomination of lead compounds for human testing and an outline of a proposed phase I human trial.

项目概要/摘要 Rac属于Rho GTPases家族，Rho GTPases是一种调节关键细胞凋亡的蛋白质。 通过整合细胞外信号和协调下游的激活来发挥功能 效应器在几种白血病模型（BCR-ABL、MLL重排和RAS突变）中， Rac是异常激活的，其基因缺失可以减弱 驱动癌基因的转化作用。此外，增加激活的Rac由于 可变剪接形式的表达或其编码序列中的突变 已经显示在一些实体瘤的恶性进展中起关键作用， 包括乳腺癌、肺癌和结肠癌以及黑色素瘤。由于其生物化学 由于Rac的性质，Rac尚未被充分开发作为癌症的治疗靶点。然而，在这方面， 一种工具化合物（NSC 23766），其在高浓度下抑制Rac活化， 哺乳动物细胞先前已经开发并抑制恶性转化 BCR-ABL介导的体外和体内研究。 在目前的项目中，威廉姆斯实验室，一个在Rho GT3生物学方面的领导者， 造血干细胞，是与Evotec（一家药物化学公司， 在药物发现方面的深厚专业知识）进行正交方法，以开发小型 用于治疗难治性白血病（特别是MLL-1）的Rac分子抑制剂 重排和RAS突变）。我们提出以下方法来确定新的 抑制剂，并将最近鉴定的化合物开发成先导分子： 1)DW_0069（先前通过虚拟色谱法鉴别的先导化合物）的优化 筛选Rac抑制剂。该化合物在体外和体内抑制Rac活化。 在体内，并且在白血病异种移植模型中耐受良好。我们已经确定 几种类似物的效力增加。在这个项目中，我们建议进一步 优化该化合物并研究其作用机制。 2)扩展Rac抑制剂的基于片段的药物发现计划，以及 开发通过基于片段的NMR筛选鉴定的额外命中。 化合物开发的优先级标准将涉及扩展的SAR研究， 良好的吸收、分布、代谢和排泄（ADME）特性和活性 在RAS突变和MLL重排的高级细胞和动物模型中， 白血病该项目提案包括一个提名先导化合物的时间轴 并概述了拟议的第一阶段人体试验。