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Targeted Small Molecule Inhibitors for Inv(16) Leukemia

Inv(16) 白血病的靶向小分子抑制剂

基本信息

批准号：
10307548
负责人：
JOHN Hackett BUSHWELLER
金额：
$ 66.72万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307548
关键词：
Acute Myelocytic Leukemia Alleles Apoptosis Binding Biochemistry Biological Availability CBFB gene CBFbeta-MYH11 fusion protein Cell model Cells Chemistry Chimeric Proteins Chromatin Chromosomal translocation Chromosome 16 Clinic Collaborations Complex Core-Binding Factor Cytotoxic Chemotherapy Data Diagnosis Distal Drug Kinetics Engraftment Enhancers Ensure Failure Generations Genes Genetic Engineering Genetic Transcription Genetically Engineered Mouse Health Hematopoiesis Human In Vitro Joints Leukemic Cell Literature MYH11 gene Malignant Neoplasms Modeling Mus Mutation Oral Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phenotype Point Mutation Population Property Publications RUNX1 gene Rattus Regimen Relapse Repression Residual Neoplasm Sampling Solubility Specificity Structure Tail Testing Time Toxic effect Translations Treatment Side Effects antileukemic activity base cancer stem cell chemotherapy improved in vivo inhibitor leukemia leukemia initiating cell leukemic stem cell mouse model novel older patient patient derived xenograft model programs promoter protein protein interaction relapse risk self-renewal small molecule small molecule inhibitor stem cell population success targeted treatment therapeutically effective transcription factor treatment response tumor

项目摘要

The gene encoding CBFβ (CBFB) is disrupted by the chromosome 16 inversion [inv(16)(p13q22)], associated with ~10% of acute myeloid leukemia (AML) in humans, resulting in a transcription factor fusion protein containing most of CBFβ fused to the coiled-coil tail region of smooth muscle myosin heavy chain (SMMHC). The CBFβ-SMMHC fusion protein acts as a dominant repressor of CBF function, binding RUNX1 and dysregulating the expression of multiple genes required for normal hematopoiesis. Current treatment utilizing cytotoxic chemotherapy results in 55% five year overall survival but only 17% for older patients. These data clearly indicate that targeted therapies that can improve the therapeutic response for inv(16) AML patients, particularly those who have relapsed or are at risk of relapse, is essential. Emerging literature suggests that inability to cure cancers with current therapies may be attributed to a population of cancer stem cells or cancer initiating cells that have long term self-renewal potential and can fully recapitulate tumor phenotype at time of relapse. Inv(16) AML is a good example of this failure because inv(16) patients invariably show, at time of relapse, the inv(16) rearrangement, while other mutations detected at diagnosis (RAS, FLT3ITD, or KIT) may or may not be detected. Our hypothesis is that small molecule inhibitors of the binding of CBFβ-SMMHC to RUNX1 could be effective therapeutic drugs that eradicate the leukemia initiating cell population in inv(16) leukemia, thereby achieving better long term survival. Recently we developed a first generation inhibitor which targets the protein-protein interaction between CBFβ-SMMHC and RUNX1. In this application, we are proposing two aims: Aim 1: Optimization of CBFβ-SMMHC inhibitors for improved potency and ADMET properties. We propose to modify our first generation inhibitor to improve ADMET properties to develop a potent orally bioavailable inhibitor for the treatment of inv(16) leukemia. Specifically, we propose to modify the structure of the linker by substitution of five-membered heterocycle based linkers in the bivalent inhibitors we have developed to improve the solubility and the oral bioavailability of the inhibitor. The most promising compounds will be profiled for pharmacokinetic properties in mice and rats, as well as using a panel of in vitro ADMET properties. The most promising compounds will be tested in Aim 2 for in vivo efficacy and efficacy against inv(16) patient samples. Aim 2: Characterization of promising CBFβ-SMMHC inhibitors using AML patient cells and mouse models for inv(16) AML. We propose to determine the efficacy and specificity of the most promising inhibitors in reducing the survival of inv(16) AML compared to non-inv(16) AML patient samples in vitro. We also propose to determine their efficacy in mice, utilizing in vivo treatment in a genetically engineered model (GEM) and a patient-derived xenograft (PDX) mouse model for inv(16) acute myeloid leukemia. The inhibitors will be tested for their antileukemic activity in reducing engraftment, leukemia latency, and leukemia burden, as well as in eliminating the leukemia stem cells in recipient mice.

编码CBFβ (CBFB)的基因被16号染色体倒位破坏[inv(16)(p13q22)]，