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Targeting defective spliceosomal pathway in myeloid malignancies

靶向骨髓恶性肿瘤中的缺陷剪接体途径

基本信息

批准号：
10434248
负责人：
VALERIA VISCONTE
金额：
$ 23.17万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
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：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434248
关键词：
3&apos Splice Site AML/MDS Acute Myelocytic Leukemia Adult Animal Model Autophagocytosis Binding Biochemical Biological Assay Cancer Model Cell Line Cell model Cells Chemicals Clinical Data Clinical Research Clonal Evolution Code Computer-Aided Design Crystallization Data Development Disease model Drug Targeting Dysmyelopoietic Syndromes Erythropoiesis Essential Genes Exhibits Future Gene Deletion Genes Glioma Goals Growth Hematopoietic Human IRAK4 gene Impairment In Vitro Intervention K-562 K562 Cells Lead Libraries Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of urinary bladder Messenger RNA Missense Mutation Modeling Mus Mutate Mutation Myeloid Cells Myeloproliferative disease NF-kappa B Oncogenic Outcome Pathway interactions Patients Pattern Pharmacology Phase I Clinical Trials Prognosis Protein Isoforms Proteins Quantitative Reverse Transcriptase PCR RNA Splicing Regulation Risk SF1 SRSF2 gene Sampling Signal Transduction Solid Neoplasm Spliceosome Assembly Pathway Spliceosomes Structure Structure-Activity Relationship Therapeutic Therapeutic Effect Therapeutic Studies Toxic effect Transgenic Mice Validation Xenograft procedure acute myeloid leukemia cell base cancer cell cancer survival chemical synthesis disease phenotype efficacy evaluation exome improved in vivo inhibitor innovation leukemia mRNA Precursor malignant breast neoplasm melanoma mouse model mutant novel novel therapeutics preclinical development preference prognostic prognostic value recruit screening small molecule therapeutics targeted agent targeted sequencing therapeutic candidate therapeutic development therapeutic target tool transcriptome transcriptomics

项目摘要

Abstract Whole-exome and targeted sequencing of MDS patients’ samples have led to discover a set of genes (SF3B1, U2AF1, SRSF2, ZRSR2 and LUC7L2) encoding mutant RNA splicing factors that alter expression patterns of protein isoforms in clonal evolution of hematopoietic cells during MDS progression. Subsequent studies found occurrences of these splicing factor mutations in AML and solid tumors. Clinical data also showed heterozygous missense mutations or hemizygous deletions of these genes are mostly mutually exclusive implying that mutations in multiple proteins in splicing regulation may be lethal in MDS cells. To date, only one compound, H3B-8800, to target SF3B1 is in phase I clinical trial to treat MDS and other myeloid malignancies. No agents targeting other mutated splicing factors are in pre-clinical development and if other mutant factors can be potential drug targets is unknown. Among them, U2AF1 mutations occurred in early MDS clones and are poor prognostic features for progression to leukemia. Studies showed U2AF1S34F hematopoietic cells and transgenic mouse models are sensitive to sudemycin that targets SF3B1. Recently, U2AF1wt was suggested to be a haplo-essential gene for the survival of cancer cells containing U2AF1 mutation. Our central hypothesis is that U2AF1wt inhibition may induce synthetic lethality to U2AF1S34F clones that depends on U2AF1wt for survival. Our rationale is that blockade of U2AF1/U2AF2 association may impair U2AF1wt function. Using fragment-based library screening, we have identified a hit compound that inhibited the U2AF1/U2AF2 binding and exhibited selective growth inhibition in K562-U2AF1S34F and human primary cells carrying U2AF1 mutations but not their wild-type counterparts. Our objective of this proposal is to develop a new class of U2AF1 inhibitors based on the hit and assess the therapeutic concept of synthetic lethality in MDS/AML disease models. Our long-term goal is to develop small-molecule therapeutics to target cancer cells defective in the spliceosome pathway. To achieve our goal, we have devised two specific aims: 1) Optimization of U2AF1 inhibitors by integrating computer-aided design with chemical syntheses; 2) Study the therapeutic effects of U2AF1 inhibitors using in vitro and in vivo U2AF1mut MDS/AML models. In Aim 1, we will improve the activity and selectivity of U2AF1 inhibitors based on the preliminary structure activity relationship and selectivity data of SF1-8 by integrating chemical syntheses, computer-aided design, biochemical assays and the co- crystal structure determination. In Aim 2, we will assess the activities of our U2AF1 inhibitors in MDS/AML cellular models, analyze transcriptome and splicing pattern changes in cell lines treated with U2AF1 inhibitors and determine the effects of our inhibitors on erythropoiesis in xenograft mouse models. Our application is innovative and significant, because it builds on our discovery of the hit to U2AF1, an emerging novel target associated with the transformation of myeloid malignancies, and has the potential to establish a new therapeutic platform to treat MDS/AML by pharmacologically targeting mutant U2AF1 cells.

摘要