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: 9176356
• 负责人: DAVID A WILLIAMS
• 金额: $ 63.82万
• 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/9176356
• 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; 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; Reading; Refractory; Relapse; Role; Sampling; Series; Signal Pathway; Signal Transduction; Solid; Solid Neoplasm; Specificity; Techniques; Testing; Therapeutic; TimeLine; Validation; Work; Xenograft Model; absorption; abstracting; analog; base; bcr-abl Fusion Proteins; 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; pre-clinical; programs; rac GTP-Binding Proteins; research clinical testing; response; rho GTP-Binding Proteins; screening; small hairpin RNA; small molecule inhibitor; stem cell biology; targeted cancer therapy; 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.

项目摘要/摘要 RAC属于调节关键细胞的Rho GTPases家族 通过整合细胞外信号并协调下游激活来发挥作用 效应子。在几种白血病模型中 白血病），RAC被异常激活，其遗传缺失可以减弱 驱动器癌基因的转化作用。此外，由于 替代剪接版本或其编码序列中突变的表达 已显示在某些实体瘤的恶性进展中起着至关重要的作用， 包括乳腺癌，肺癌和结肠癌以及黑色素瘤。由于其生化 属性，RAC尚未被充分利用为癌症的治疗靶标。然而， 一种工具化合物（NSC 23766），可在高浓度下抑制RAC激活 哺乳动物细胞先前已经开发并抑制恶性转化 由BCR-ABL在体外和体内介导。 在本项目中，威廉姆斯实验室，Rho GTPase生物学领导者 造血干细胞与EVOTEC（一家药物化学公司 在药物发现方面的深厚专业知识）进行正交的方法来发展小型 RAC的分子抑制剂治疗难治性白血病（特别是MLL- 重新排列和RAS突变）。我们建议采用以下方法来识别新的 抑制剂并将最近鉴定为铅分子的化合物： 1）优化DW_0069，先前由虚拟标识的铅化合物 筛选RAC抑制剂。这种复合抑制了RAC在体外和 体内，在白血病异种移植模型中耐受性良好。我们已经确定了 几个类似物具有增加的效力。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理。 2）扩展针对RAC抑制剂的基于碎片的药物发现计划，以及 通过基于片段的NMR屏幕确定的其他命中的开发。 优先考虑复合开发的标准将涉及扩展的SAR研究， 良好的吸收，分布，代谢和排泄物（ADME）特性和活性 在RAS突变和MLL的高级细胞和动物模型中 白血病。该项目建议包括提名铅化合物的时间表 用于人类测试和提议的I期人类试验的概述。