Department of Pharmacological & Pharmaceutical Sciences, University of Houston, 4849 Calhoun Rd, Health Building 2, Room 7033, Houston, TX 77204-5037, USA.
Department of Pharmacological & Pharmaceutical Sciences, University of Houston, 4849 Calhoun Rd, Health Building 2, Room 7033, Houston, TX 77204-5037, USA; Department of Cancer Systems Imaging, MD Anderson Cancer Center, 1881 East Road, Houston, TX 77030-4009, USA.
Bioorg Med Chem Lett. 2020 Dec 1;30(23):127552. doi: 10.1016/j.bmcl.2020.127552. Epub 2020 Sep 15.
The importance of ERK5 kinase signaling in tumorigenicity, metastasis, and drug resistance of cancer stem cells (CSCs) has been recognized recently, and we report a unique dual inhibitor that blocks binding of the ERK5 activator and ERK5 autophosphorylation simultaneously. The conventional ATP-binding site inhibitors have not yet yielded expected level of anti-cancer effects, due to complexities in converting ERK5 activation into CSC biological effects. We designed the first ERK5-targeted anti-CSC dual active hetero-bivalent inhibitor that blocks the regulatory peptide interaction involved in ERK5 kinase activation and that simultaneously inhibits the conventional ATP-binding pocket as well. We utilized two assay systems to independently prove disruption of these two ERK5 activities via a single compound. We also showed that this compound inhibited CSC activities, such as colony formation, cell proliferation, and migration.
最近，ERK5 激酶信号在肿瘤发生、转移和癌症干细胞（CSC）耐药性中的重要性得到了认可，我们报告了一种独特的双重抑制剂，它可以同时阻断 ERK5 激活剂的结合和 ERK5 的自身磷酸化。由于将 ERK5 激活转化为 CSC 生物学效应的复杂性，传统的 ATP 结合位点抑制剂尚未产生预期的抗癌效果。我们设计了第一个针对 ERK5 的靶向抗 CSC 双重活性杂双价抑制剂，可阻断涉及 ERK5 激酶激活的调节肽相互作用，同时抑制常规的 ATP 结合口袋。我们利用两个检测系统通过单个化合物独立证明了这两种 ERK5 活性的中断。我们还表明，该化合物抑制了 CSC 活性，如集落形成、细胞增殖和迁移。
