Alvocidib 通过抑制 CILK1 对初级纤毛的调节。

Modulation of Primary Cilia by Alvocidib Inhibition of CILK1.

机构信息

Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.

Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.

出版信息

Int J Mol Sci. 2022 Jul 23;23(15):8121. doi: 10.3390/ijms23158121.

DOI:10.3390/ijms23158121

PMID:35897693

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9329819/

Abstract

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.

摘要

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。