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

描述（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，开发针对抗凋亡Bcl-2蛋白BH3结合槽的抗癌药物已成为一个有希望但困难的目标。最初针对Bcl-xL结构的化合物，从而能够与Bcl-2、Bcl-xL和Bcl-W结合，在临床中显示出治疗癌症的希望，尽管研究发现，Mcl-1过表达会使癌症逃避治疗。为此，最近针对Bcl-2的稳定和细胞渗透性钉接BH3肽的成功为鉴定能够选择性结合Mcl-1的肽序列提供了动力，这是本提案的主要目的之一。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药物。为了验证我们的假设，我们将描述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化合物的潜在抗癌活性。

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.