权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

A high-throughput screen for inhibitors of Plk1-interacting checkpoint helicase (PICH)

Plk1 相互作用检查点解旋酶 (PICH) 抑制剂的高通量筛选

基本信息

批准号：
10356280
负责人：
Yoshiaki Azuma
金额：
$ 19.19万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356280
关键词：
ATP phosphohydrolase Alleles Anaphase Animal Cancer Model Antineoplastic Agents Area Auxins Biochemical Biological Assay Breast Cancer Cell Cell Death Cell Differentiation process Cell Line Cell Proliferation Cessation of life Characteristics Chromatin Chromatin Remodeling Factor Chromosomal Instability Chromosome Segregation Collection DNA DNA-dependent ATPase Development Dose Drug Targeting Engineering Evaluation Family Family member Frequencies Genome Goals Human Cell Line Human Cloning Human Engineering In Vitro Intercalating Agents Lead Malignant Neoplasms Microtubules Mitosis Mitotic Normal Cell Normal tissue morphology Outcome Patient-Focused Outcomes Phenotype Positioning Attribute Process Proteins Research Research Subjects Role Secondary to Testing Therapeutic Tissues Transcriptional Regulation Ultrafine Validation Work base cancer cell cancer therapy cancer type cell type cheminformatics chromosome loss cytotoxicity detection assay dosage ds-DNA helicase high throughput screening improved inhibitor new therapeutic target novel overexpression response screening small molecule small molecule inhibitor small molecule libraries therapeutic target tool translocase transmission process triple-negative invasive breast carcinoma

项目摘要

Project Summary/Abstract Recent studies have shown that PIk1-interacting checkpoint helicase (PICH) is a potential cancer therapeutic target. PICH has critical functions in mitosis for the fidelity of chromosome segregation and without PICH there is an increased frequency of Ultra-Fine DNA Bridges (UFBs) in anaphase, which results in multi-nucleation and chromosome loss. Other proteins with key functions in mitosis, and that are required for accurate chromosome segregation, have proven to be effective targets of cancer drugs. For example, drugs that target microtubule dynamics. Importantly, PICH was found to be over-expressed in breast cancer cells and depletion of PICH was found to be extremely toxic to triple negative breast cancer cells, while not affecting matched normal tissue. Because PICH is over-expressed in a range of cancers, it is likely that many cancer types require PICH function for survival. Therefore, small molecule PICH inhibitors have potential for improved patient outcomes in cancer therapy. However, no inhibitors of PICH have been identified. Here we propose to identify selective PICH inhibitors and determine their cytotoxicity towards a range of cancer types in which PICH is over- expressed. Since PICH is a dsDNA-dependent ATPase, it has an activity suitable for high-throughput screening (HTS) for inhibitors using diverse small molecule libraries. We have established biochemical purification of active PICH and we have devised strategies and generated the tools that will allow primary hits from the HTS to be efficiently subjected to secondary screening, to validate bona fide PICH inhibitors and to eliminate non-specific inhibitors. The cellular consequences of PICH inhibition will be determined to fully characterize the effects on normal and cancer cells. Cytotoxicity studies will determine which cancer types can be selectively killed by the inhibitors and we will define the dosages required. The outcomes will be selective small molecule PICH inhibitors that will be valuable research tools and will be lead compounds for development of optimally potent molecules ahead of studies in animal cancer models.

项目总结/文摘