PDF(Pubmed)
Abstract：
The trafficking chaperone PDE6D (or PDEδ) was proposed as a surrogate target for K-Ras, leading to the development of a series of inhibitors that block its prenyl binding pocket. These inhibitors suffered from low solubility and suspected off-target effects, preventing their clinical development. Here, we developed a highly soluble, low nanomolar PDE6D inhibitor (PDE6Di), Deltaflexin3, which has the lowest off-target activity as compared to three prominent reference compounds. Deltaflexin3 reduces Ras signaling and selectively decreases the growth of KRAS mutant and PDE6D-dependent cancer cells. We further show that PKG2-mediated phosphorylation of Ser181 lowers K-Ras binding to PDE6D. Thus, Deltaflexin3 combines with the approved PKG2 activator Sildenafil to more potently inhibit PDE6D/K-Ras binding, cancer cell proliferation, and microtumor growth. As observed previously, inhibition of Ras trafficking, signaling, and cancer cell proliferation remained overall modest. Our results suggest reevaluating PDE6D as a K-Ras surrogate target in cancer.
摘要：
提出了贩运伴侣PDE6D（或PDEδ）作为K-Ras的替代目标，导致一系列抑制剂的发展，阻止其异戊二烯结合口袋。这些抑制剂具有低溶解度和可疑的脱靶效应，阻止其临床发展。这里,我们开发了一种高度可溶的，低纳摩尔PDE6D抑制剂（PDE6Di），Deltaflexin3,其与三种突出的参考化合物相比具有最低的脱靶活性。Deltaflexin3降低Ras信号传导并选择性降低KRAS突变体和PDE6D依赖性癌细胞的生长。我们进一步显示PKG2介导的Ser181磷酸化降低了K-Ras与PDE6D的结合。因此，Deltaflexin3结合批准的PKG2激活剂西地那非更有效地抑制PDE6D/K-Ras结合，癌细胞增殖，和微肿瘤生长。如前所述，禁止拉斯贩运，信令,和癌细胞增殖总体保持适度。我们的结果表明重新评估PDE6D作为癌症中的K-Ras替代靶标。
