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Mcl-1 in apoptosis and signal transduction: a structure/function approach

Mcl-1 在细胞凋亡和信号转导中的作用：结构/功能方法

基本信息

批准号：
8373785
负责人：
Maurizio Pellecchia
金额：
$ 54.54万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-09 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8373785
关键词：
Antisense Oligonucleotides Apoptosis Apoptosis Regulator Apoptotic B-Cell Lymphomas BH3 peptide Binding Binding Proteins Cell Culture Techniques Cell Death Cell Survival Cell model Cells Chronic Lymphocytic Leukemia Clinic Clinical Clinical Treatment Clinical Trials Complex Data Defect Development Dimerization Exhibits Family Family member Goals Human Innovative Therapy Laboratories Libraries Lymphoma MCL1 protein Malignant Neoplasms Malignant neoplasm of prostate Mediating Molecular Multiple Myeloma Oblimersen Pathway interactions Peptide Phage Display Library Peptides Physiological Protein Binding Protein Family Proteins Radiation Randomized Regulation Reporting Resistance Role Signal Transduction Solid Neoplasm Structure Surface System Testing anti-cancer therapeutic base cancer cell cancer therapy chemotherapy design drug candidate drug discovery in vivo in vivo Model inhibitor/antagonist innovation leukemia/lymphoma melanoma member mimetics mouse model novel pro-apoptotic protein protein aminoacid sequence success therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Given the pivotal role of anti-apoptotic Bcl-2 family proteins in cancer cell survival, development of anti-cancer therapeutics targeting the BH3 binding groove of anti-apoptotic Bcl-2 proteins has emerged as a promising, but difficult goal. Initial compounds targeted to the structure of Bcl-xL, and thereby able to bind to Bcl-2, Bcl-xL and Bcl-W, have shown promise in the clinic for the treatment of cancer, though studies have discovered that Mcl-1 over-expression allows cancers to evade treatment. To this end, the recent success with stable and cell permeable stapled BH3 peptides targeting Bcl-2 has provided the impetus to identify peptide sequences capable of selectively binding to Mcl-1 which is one major Aim of this proposal. If successful, our studies could result in advanced clinical candidates for the treatment of cancer. To test our hypotheses we will characterize and further determine the structural basis for inhibition, and subsequently we will test the potential anti-cancer activity of the proposed compounds in advanced pharmacological studies in cell and mice models of prostate cancer. PUBLIC HEALTH RELEVANCE: Our studies are aimed at the identification of natural peptide sequences that target selectively an anti-apoptotic protein, Mcl-1, responsible for the onset of progression of most solid tumors. We will first characterize at the molecular level the structural basis for inhibition of Mcl-1, and subsequently we will test the potential anti- cancer activity of the proposed compounds in advanced pharmacological studies in cell and mice models of prostate cancer.

描述（由申请人提供）：鉴于抗凋亡Bcl-2家族蛋白在癌细胞存活中的关键作用，靶向抗凋亡Bcl-2蛋白的BH 3结合沟的抗癌治疗剂的开发已经成为一个有前景但困难的目标。靶向Bcl-xL结构的初始化合物，从而能够结合Bcl-2，Bcl-xL和Bcl-W，在临床上显示出治疗癌症的前景，尽管研究发现Mcl-1过表达允许癌症逃避治疗。为此，最近成功地用稳定的和细胞可渗透的钉合的BH 3肽靶向Bcl-2提供了动力，以鉴定能够选择性地结合Mcl-1的肽序列，这是该提议的一个主要目的。如果成功，我们的研究可能会导致癌症治疗的高级临床候选人。为了验证我们的假设，我们将表征并进一步确定抑制的结构基础，随后我们将在前列腺癌细胞和小鼠模型的高级药理学研究中测试所提出的化合物的潜在抗癌活性。公共卫生关系：我们的研究旨在鉴定选择性靶向抗凋亡蛋白Mcl-1的天然肽序列，Mcl-1负责大多数实体瘤的进展。我们将首先在分子水平上表征抑制Mcl-1的结构基础，随后我们将测试Mcl-1的潜在抗癌活性。在前列腺癌的细胞和小鼠模型中的先进药理学研究中提出的化合物。