Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Dr., San Diego, California 92121, United States.
J Med Chem. 2021 Apr 22;64(8):4857-4869. doi: 10.1021/acs.jmedchem.0c02152. Epub 2021 Apr 6.
LONP1 is an AAA+ protease that maintains mitochondrial homeostasis by removing damaged or misfolded proteins. Elevated activity and expression of LONP1 promotes cancer cell proliferation and resistance to apoptosis-inducing reagents. Despite the importance of LONP1 in human biology and disease, very few LONP1 inhibitors have been described in the literature. Herein, we report the development of selective boronic acid-based LONP1 inhibitors using structure-based drug design as well as the first structures of human LONP1 bound to various inhibitors. Our efforts led to several nanomolar LONP1 inhibitors with little to no activity against the 20S proteasome that serve as tool compounds to investigate LONP1 biology.
LONP1 是一种 AAA+ 蛋白酶，通过去除受损或错误折叠的蛋白质来维持线粒体的稳态。LONP1 活性和表达的升高促进了癌细胞的增殖，并使其对凋亡诱导试剂产生抗性。尽管 LONP1 在人类生物学和疾病中非常重要，但文献中仅描述了很少的 LONP1 抑制剂。在此，我们报告了使用基于结构的药物设计开发的选择性硼酸基 LONP1 抑制剂，以及人 LONP1 与各种抑制剂结合的首个结构。我们的努力得到了几种对 20S 蛋白酶体几乎没有活性的纳摩尔级 LONP1 抑制剂，它们可用作研究 LONP1 生物学的工具化合物。
