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

基本信息

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
项目类别：
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

项目摘要

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 是调节关键细胞的蛋白质通过整合细胞外信号和协调下游信号的激活来发挥作用效应器。在多种白血病模型（BCR-ABL、MLL 重排和 RAS 突变）中白血病），Rac 被异常激活，其基因缺失可以减弱驱动癌基因的转化作用。此外，Rac 的激活增加是由于选择性剪接版本的表达或其编码序列中的突变已被证明在一些实体瘤的恶性进展中发挥关键作用，包括乳腺癌、肺癌、结肠癌以及黑色素瘤。由于其生化由于 Rac 的特性，Rac 尚未被充分开发作为癌症的治疗靶点。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开发并抑制恶性转化体外和体内均由 BCR-ABL 介导。在本项目中，威廉姆斯实验室（Rho GTPase 生物学领域的领导者）造血干细胞，正在与 Evotec（一家药物化学公司，药物发现方面的深厚专业知识）进行正交方法来开发小型药物 Rac 分子抑制剂用于治疗难治性白血病（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发现的化合物开发成先导分子： 1) 对 DW_0069 的优化，该先导化合物先前由虚拟筛选 Rac 抑制剂。该化合物在体外和体内抑制 Rac 激活体内，并且在白血病异种移植模型中具有良好的耐受性。我们已经确定了几种效力增强的类似物。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) 扩展基于片段的 Rac 抑制剂药物发现计划，以及开发通过基于片段的 NMR 屏幕识别的其他命中。化合物开发的优先顺序标准将涉及扩展的 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。项目提案包括先导化合物提名的时间表用于人体测试和拟议的第一阶段人体试验的概要。