Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
Int J Mol Sci. 2022 Jul 23;23(15):8121. doi: 10.3390/ijms23158121.
The primary cilium provides cell sensory and signaling functions. Cilia structure and function are regulated by ciliogenesis-associated kinase 1 (CILK1). Ciliopathies caused by mutations show longer cilia and abnormal Hedgehog signaling. Our study aimed to identify small molecular inhibitors of CILK1 that would enable pharmacological modulation of primary cilia. A previous screen of a chemical library for interactions with protein kinases revealed that Alvocidib has a picomolar binding affinity for CILK1. In this study, we show that Alvocidib potently inhibits CILK1 (IC = 20 nM), exhibits selectivity for inhibition of CILK1 over cyclin-dependent kinases 2/4/6 at low nanomolar concentrations, and induces CILK1-dependent cilia elongation. Our results support the use of Alvocidib to potently and selectively inhibit CILK1 to modulate primary cilia.
初级纤毛提供细胞感觉和信号功能。纤毛的结构和功能受纤毛发生相关激酶 1（CILK1）调节。由 突变引起的纤毛病显示出更长的纤毛和异常的 Hedgehog 信号。我们的研究旨在鉴定 CILK1 的小分子抑制剂，从而能够对初级纤毛进行药理学调节。先前对蛋白激酶相互作用的化学文库进行筛选，结果表明 Alvocidib 对 CILK1 的结合亲和力为皮摩尔级。在这项研究中，我们表明 Alvocidib 能够强烈抑制 CILK1（IC = 20 nM），在低纳摩尔浓度下对 CILK1 表现出选择性抑制，而对细胞周期蛋白依赖性激酶 2/4/6 的抑制作用较低，并且诱导 CILK1 依赖性纤毛伸长。我们的结果支持使用 Alvocidib 来强烈且选择性地抑制 CILK1 以调节初级纤毛。
