Small molecules modulating RNA-binding protein Msi1

调节 RNA 结合蛋白 Msi1 的小分子

• 批准号: 9136068
• 负责人: KRISTI L NEUFELD
• 金额: $ 43.25万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9136068
• 关键词: Affect; Apoptosis; Binding; Binding Proteins; Biological Assay; Cancer Cell Growth; Cancer cell line; Cell Cycle Progression; Cell Line; Cell Survival; Chemicals; Colorectal Cancer; Cyclin-Dependent Kinases; Data; Development; Feedback; Fluorescence Polarization; Gene Targeting; Genes; Health; Homeostasis; Human; In Vitro; Intestines; Knock-in; Knockout Mice; Lead; Malignant Neoplasms; Messenger RNA; Modeling; Molecular; Mus; NOD/SCID mouse; Notch and Wnt Signaling Pathway; Nuclear Magnetic Resonance; Oncogenes; Pharmaceutical Chemistry; Pharmaceutical Preparations; RNA; RNA Binding; RNA-Binding Proteins; RNA-Protein Interaction; Radiation; Reporter; Reporting; Resistance; Role; Series; Signal Transduction; Staging; Staining method; Stains; Stem cells; Structure; Structure-Activity Relationship; Surface Plasmon Resonance; Testing; Therapeutic; Translations; Tumor Suppressor Proteins; Validation; Western Blotting; Xenograft Model; aldehyde dehydrogenase 1; base; cancer cell; cancer initiation; cancer therapy; cancer type; chemotherapy; colon cancer cell line; cytotoxicity; design; drug development; drug discovery; high throughput screening; in vivo; inhibitor/antagonist; knock-down; malignant breast neoplasm; molecular targeted therapies; mouse model; nanomolar; notch protein; novel; overexpression; preclinical study; small molecule; small molecule inhibitor; tumor; tumor progression

DESCRIPTION (provided by applicant): Musashi-1 (Msi1) is a stem cell marker overexpressed in many types of cancers. Msi1 is an RNA-binding protein (RBP) that binds to and inhibits translation of target mRNAs. This inhibition results in activation of Wnt and Notch signaling and consequently, cell cycle progression, survival, and resistance to programmed cell death. Experimental manipulation to reduce Msi1 levels in breast and colon cancer cell lines leads to tumor regression in mouse xenograft models. Because Msi1 stimulates both Notch and Wnt signaling and is overexpressed in a wide variety of cancers, Msi1 is an attractive target for developing novel cancer therapy. So far there are no reported small molecule inhibitors of the Msi1-RNA interaction. RBPs such as Msi1 are considered "undruggable" due to the lack of a well-defined binding pocket for target RNA. Through high throughput screening, we have obtained initial hits at nanomolar Ki, which are validated by Surface Plasmon Resonance (SPR) and Nuclear Magnetic Resonance (NMR). Our hypothesize that small molecule compounds that disrupt Msi1-RNA binding will block Msi1 function, leading to translation of target genes that are critical for inhibiting cancer cell growth and progression. Our objective is to obtain a series of small molecule compounds as chemical probes that potently bind to Msi1 and modulate its function, and ultimately select 1-2 most drug- like lead compounds for further development as a whole new class of molecular cancer therapy that inhibit cancer with Msi1 overexpression. To test our hypothesis, three Specific Aims will be carried out: AIM 1, Structure-based rational design and lead optimization of Msi1-inhibitors; AIM 2, In vitro anti-tumor activity, target validation, and mechanism of action studies; AIM 3, In vivo efficacy studies of the lead Msi1-inhibitors in xenograft models of human cancer. Overall Impact: Successfully carried out, this project will discover novel chemical probes for Msi1 and potentially lead compounds as Msi1-inhibitors that inhibit cancer cells with high levels of Msi1-Notch/Wnt signaling. Discovery of such Msi1-inhibitors will: (1) provide potent and useful chemical probes for delineating the functional roles of Msi1-Notch/Wnt signaling in cancer initiation and progression; and (2) provide promising lead compounds to develop novel molecular therapeutics targeting the oncoprotein Msi1. The data and leads obtained will enable us to seek out partners for further drug discovery and development studies. After assessing structure-activity relationships and lead optimization, we may obtain a few lead compounds for further development as a whole new class of molecular cancer therapeutics that inhibit specific protein/RNA interactions required for cancer cell survival and progression.

描述（由申请人提供）：Musashi-1（Msi 1）是一种在许多类型的癌症中过表达的干细胞标志物。Msi 1是一种RNA结合蛋白（RBP），可结合并抑制靶mRNA的翻译。这种抑制导致Wnt和Notch信号传导的激活，并因此导致细胞周期进展、存活和对程序性细胞死亡的抗性。降低乳腺癌和结肠癌细胞系中Msi 1水平的实验操作导致小鼠异种移植模型中的肿瘤消退。由于Msi 1刺激Notch和Wnt信号传导，并且在多种癌症中过表达，因此Msi 1是开发新型癌症治疗的有吸引力的靶标。 到目前为止，还没有报道Msi 1-RNA相互作用的小分子抑制剂。RBP如Msi 1被认为是“不可用药的”，因为缺乏明确定义的靶RNA结合口袋。通过高通量筛选，我们已经获得了纳摩尔Ki的初始命中，其通过表面等离子体共振（SPR）和核磁共振（NMR）进行验证。我们假设，破坏Msi 1-RNA结合的小分子化合物将阻断Msi 1功能，导致对抑制癌细胞生长和进展至关重要的靶基因的翻译。我们的目标是获得一系列小分子化合物作为化学探针，其有效地结合Msi 1并调节其功能，并最终选择1-2个最药物样的先导化合物用于进一步开发，作为一类全新的分子癌症治疗，抑制Msi 1过表达的癌症。 为了验证我们的假设，将进行三个特定目标：AIM 1，基于结构的合理设计和Msi 1抑制剂的先导优化; AIM 2，体外抗肿瘤活性、靶标验证和作用机制研究; AIM 3，先导Msi 1抑制剂在人类癌症异种移植模型中的体内疗效研究。 总体影响：该项目的成功实施将发现Msi 1的新型化学探针，并可能发现作为Msi 1抑制剂的潜在先导化合物，这些化合物可抑制具有高水平Msi 1-Notch/Wnt信号的癌细胞。发现这样的Msi 1抑制剂将：（1）提供有效和有用的化学探针，用于描绘Msi 1-Notch/Wnt信号传导在癌症发生和发展中的功能作用;和（2）提供有前途的先导化合物，以开发靶向癌蛋白Msi 1的新分子治疗剂。获得的数据和线索将使我们能够为进一步的药物发现和开发研究寻找合作伙伴。在评估结构-活性关系和先导化合物优化后，我们可能会获得一些先导化合物，用于进一步开发，作为一类全新的分子癌症治疗剂，抑制癌细胞存活和进展所需的特定蛋白质/RNA相互作用。

项目成果

Human oncoprotein Musashi-2 N-terminal RNA recognition motif backbone assignment and identification of RNA-binding pocket.

• DOI: 10.18632/oncotarget.22540
• 发表时间: 2017-12-05
• 期刊: Oncotarget
• 作者: Lan L;Xing M;Douglas JT;Gao P;Hanzlik RP;Xu L
• 通讯作者: Xu L

Time-lapse live cell imaging to monitor doxorubicin release from DNA origami nanostructures.

• DOI: 10.1039/c7tb03223d
• 发表时间: 2018-03-21
• 期刊: Journal of materials chemistry. B
• 作者: Zeng Y;Liu J;Yang S;Liu W;Xu L;Wang R
• 通讯作者: Wang R

MicroRNA-383 acts as a tumor suppressor in colorectal cancer by modulating CREPT/RPRD1B expression.

MicroRNA-383 通过调节 CREPT/RPRD1B 表达作为结直肠癌肿瘤抑制因子

• DOI: 10.1002/mc.22866
• 发表时间: 2018-10
• 期刊: Molecular carcinogenesis
• 影响因子: 4.6
• 作者: Li J;Smith AR;Marquez RT;Li J;Li K;Lan L;Wu X;Zhao L;Ren F;Wang Y;Wang Y;Jia B;Xu L;Chang Z
• 通讯作者: Chang Z