Generation of Pim kinase inhibitors based on structural and post-transcriptional analysis

丝氨酸/苏氨酸激酶Pim-1在细胞周期进程和细胞凋亡抑制中起重要作用，导致前列腺肿瘤的发生。因此，Pim-1抑制有望成为开发新的抗癌药物的一个有吸引力的靶点。然而，由于缺乏特异性，针对Pim-1的小化合物尚未进入临床应用。在1.6 A分辨率下，我们分析了p27^<Kip1>肽配合物中的Pim-1的x射线晶体结构。通过添加8个精氨酸残基R8，我们得到了一个新的细胞渗透性p27^<Kip1>肽，该肽可以干扰Pim-1与其底物的结合，并作为抗癌药物。用该肽治疗前列腺癌DU145诱导G1阻滞和随后的体外细胞凋亡。该肽在体内前列腺癌异种移植模型中也能抑制肿瘤生长。

The serine/threonine kinase Pim-1 plays an important role in cell cycle progression and apoptosis inhibition, resulting in prostate tumorigenesis. Therefore, Pim-1 inhibition has been expected to be an attractive target for developing new anti-cancer drugs. However, no small compounds targeting Pim-1 have progressed to clinical use because of their lack of specificity. Here we analyzed the X-ray crystal structure of Pim-1 in complex with p27^<Kip1> peptide at 1.6 A resolution. Adding eight tandem Arg residues, R8, we generated a new cell-permeable Pim-1-inhibitory p27^<Kip1> peptide that could interfere with the binding of Pim-1 to its substrates and act as an anti-cancer drug. Treatment of prostate cancer DU145 with the peptide induces G1 arrest and subsequently apoptosis in vitro. The peptide could also inhibit tumor growth in in vivo prostate cancer xenograft models.