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

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。 公共卫生相关性：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。

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.