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Understanding the mechanism of action for anticancer sulfonamides that target splicing

了解靶向剪接的抗癌磺胺类药物的作用机制

基本信息

批准号：
10372016
负责人：
DEEPAK NIJHAWAN
金额：
$ 36.66万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372016
关键词：
Advanced Malignant Neoplasm Alleles Binding Biology Cancer Cell Growth Cause of Death Cell Death Cells Chloroquinoxaline Sulfonamide Complex Critical Pathways Cullin Proteins Data Defect Dependence Development Drug Targeting Exons FDA approved Gene Expression Genes Goals Human Immunomodulators Introns Knowledge Libraries Ligase Malignant Neoplasms Mutation Oncogenic Pathway interactions Patients Pharmaceutical Preparations Phenotype Pre-Clinical Model Protein Family Proteins Publishing RNA Binding RNA Splicing Research Resistance Sulfonamides Testing Thalidomide Ubiquitin Ubiquitination United States Work anti-cancer anticancer activity base cancer cell cancer therapy cell growth cellular targeting clinical development experimental study genome-wide analysis human model inhibitor lenalidomide mRNA Precursor member new therapeutic target novel therapeutics pleiotropism programs receptor recruit resistance mutation small molecule tumor ubiquitin ligase ubiquitin-protein ligase

项目摘要

Project Summary / Abstract In spite of recent advances, cancer remains a leading cause of death in the United States, and there is an urgent need for new therapies. Genome-wide studies of hundreds of human tumors have revealed pre-mRNA splicing as a critical pathway for cancer cell growth, and thus an attractive target for new therapies. Many of the proteins involved with pre-mRNA splicing lack enzymatic activity, and therefore are unusually difficult to target with small molecule drugs. We have recently discovered a class of anticancer sulfonamides that target pre-mRNA splicing which we refer to as SPLAMs (SPLicing inhibitor sulfonAMides). SPLAMs act by recruiting RBM39 (RNA binding motif 39) as a neo-substrate to DCAF15 (DDB1/CUL Associated Factor 15). DCAF15 is part of a CUL4 E3 ubiquitin ligase receptor complex. As a consequence, recruitment of RBM39 to DCAF15 leads to RBM39 ubiquitination and proteasomal degradation. RBM39 is important for pre-mRNA splicing of select introns and exons. Therefore, as a consequence of SPLAM treatment, RBM39 degradation leads to pre-mRNA splicing defects. The mechanism of action of SPLAMs is similar to the FDA approved drugs, thalidomide and lenalidomide (also known as IMiDs). IMiDs recruit neo- substrates to cereblon, which is another member of the DCAF family of proteins. IMiD binding to CRBN has pleiotropic effects which are either the result of targeting unique neo-substrates or inhibiting the endogenous activity of cereblon. Currently, it is not known as to what effects SPLAM binding to DCAF15 has on alternative neo-substrates and endogenous activity. In our first aim, we propose to identify a DCAF15 mutation that is resistant to SPLAMs in order to identify on-target cellular pathways influenced by SPLAMs. In our second aim, we propose a set of experiments to identify both DCAF15 endogenous substrates as well as neo-substrates other than RBM39. The clinical development of a SPLAM based therapy will require identifying which patients are most likely to respond. We have found that RBM39 degradation only causes cell death in a subset of cancer cells. In our final aim, we propose a set of experiments to understand the basis for this selectivity by studying the function of RBM39 in SPLAM-sensitive and insensitive cells. In particular, our preliminary data suggests that cancer cells with mutations in splicing factors that are also found in human cancers are sensitive to SPLAMs. We propose a set of experiments to study RBM39 biology and SPLAM sensitivity in models of human cancer harboring these splicing mutations.

项目摘要/摘要