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

描述(申请人提供)：鉴于抗凋亡的Bcl-2家族蛋白在癌细胞生存中的关键作用，以抗凋亡的Bcl-2蛋白的BH3结合槽为靶点的抗癌疗法的发展已成为一个有希望但困难的目标。尽管研究发现Mcl-1的过度表达允许癌症逃脱治疗，但最初的化合物靶向于Bclxl的结构，从而能够与Bcl2、Bclxl和BclW结合，在临床上显示出治疗癌症的前景。为此，最近针对Bcl-2的稳定且细胞可渗透的BH3多肽的成功为寻找能够选择性结合Mcl-1的多肽序列提供了动力，这也是本方案的主要目标之一。如果成功，我们的研究可能会产生治疗癌症的高级临床候选药物。为了验证我们的假设，我们将表征并进一步确定抑制作用的结构基础，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建议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.