Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
PLoS Comput Biol. 2023 May 26;19(5):e1010263. doi: 10.1371/journal.pcbi.1010263. eCollection 2023 May.
PNCK, or CAMK1b, is an understudied kinase of the calcium-calmodulin dependent kinase family which recently has been identified as a marker of cancer progression and survival in several large-scale multi-omics studies. The biology of PNCK and its relation to oncogenesis has also begun to be elucidated, with data suggesting various roles in DNA damage response, cell cycle control, apoptosis and HIF-1-alpha related pathways. To further explore PNCK as a clinical target, potent small-molecule molecular probes must be developed. Currently, there are no targeted small molecule inhibitors in pre-clinical or clinical studies for the CAMK family. Additionally, there exists no experimentally derived crystal structure for PNCK. We herein report a three-pronged chemical probe discovery campaign which utilized homology modeling, machine learning, virtual screening and molecular dynamics to identify small molecules with low-micromolar potency against PNCK activity from commercially available compound libraries. We report the discovery of a hit-series for the first targeted effort towards discovering PNCK inhibitors that will serve as the starting point for future medicinal chemistry efforts for hit-to-lead optimization of potent chemical probes.
PNCK，也称为 CAMK1b，是钙调蛋白依赖性激酶家族中研究较少的激酶，最近在几项大规模多组学研究中被确定为癌症进展和生存的标志物。PNCK 的生物学及其与肿瘤发生的关系也开始被阐明，数据表明其在 DNA 损伤反应、细胞周期控制、细胞凋亡和 HIF-1-α相关途径中具有多种作用。为了进一步探索 PNCK 作为临床靶点，必须开发有效的小分子分子探针。目前，CAMK 家族在临床前或临床研究中没有靶向小分子抑制剂。此外，PNCK 也不存在实验衍生的晶体结构。在此，我们报告了一项三管齐下的化学探针发现活动，该活动利用同源建模、机器学习、虚拟筛选和分子动力学从商业上可获得的化合物库中鉴定出对 PNCK 活性具有低微摩尔效力的小分子。我们报告了发现针对 PNCK 抑制剂的首次靶向努力的命中系列，这将作为未来药物化学努力的起点，以优化有效的化学探针的先导化合物优化。
