Cellular and molecular effects of PNCK, a non-canonical kinase target in renal cell carcinoma

Essegian, Derek J.; Chávez, Valery; Bustamante, Floritza; Schürer, Stephan C.; Merchan, Jaime R.

doi:10.1016/j.isci.2022.105621

Cited by 2 publications

(2 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, high expression correlated significantly with survival, tumor size and histological grade in all kidney cancer cohorts. We have previously shown PNCK to play roles in angiogenesis, apoptosis, DNA damage and cell cycle control pathways [ 13 ]. To further study the biological relevance of PNCK in vitro and validate this kinase as a novel target, an AI-assisted chemical probe discovery campaign was initiated.…”

Section: Introductionmentioning

confidence: 99%

AI-Assisted chemical probe discovery for the understudied Calcium-Calmodulin Dependent Kinase, PNCK

et al. 2023

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

AI-Assisted chemical probe discovery for the understudied Calcium-Calmodulin Dependent Kinase, PNCK

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…The pregnancy-upregulated non-ubiquitous calmodulin kinase Pnck [ 90 ], also denoted as calmodulin-dependent kinase Iβ2 (CaMK-Iβ2) with structural similarities to CaMK-I, is overexpressed in different tumors [ 91 , 92 , 93 , 94 , 95 ], including renal, nasopharyngeal, hepatocellular and breast carcinomas, and provably among other cancer types, increasing their aggressiveness and poor prognosis. As in other tumors, Pnck is co-overexpressed with amplified ErbB2 in more than 30% of human estrogen receptor-negative breast carcinomas [ 94 ].…”

Section: Erbb Receptor Signaling and Cam-dependent Protein Kinasesmentioning

confidence: 99%

Regulation of ErbB Receptors by the Ca2+ Sensor Protein Calmodulin in Cancer

Villalobo

2023

Biomedicines

View full text Add to dashboard Cite

Overexpression and mutations of the epidermal growth factor receptor (EGFR/ErbB1/HER1) and other tyrosine kinase receptors of the ErbB family (ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4) play an essential role in enhancing the proliferation, the migratory capacity and invasiveness of many tumor cells, leading to cancer progression and increased malignancy. To understand these cellular processes in detail is essential to understand at a molecular level the signaling pathways and regulatory mechanisms controlling these receptors. In this regard, calmodulin (CaM) is a Ca2+-sensor protein that directly interacts with and regulates ErbB receptors, as well as some CaM-dependent kinases that also regulate these receptors, particularly EGFR and ErbB2, adding an additional layer of CaM-dependent regulation to this system. In this short review, an update of recent advances in this area is presented, covering the direct action of Ca2+/CaM on the four ErbB family members mostly in tumor cells and the indirect action of Ca2+/CaM on the receptors via CaM-regulated kinases. It is expected that further understanding of the CaM-dependent mechanisms regulating the ErbB receptors in future studies could identify new therapeutic targets in these systems that could help to control or delay cancer progression.

show abstract

Cellular and molecular effects of PNCK, a non-canonical kinase target in renal cell carcinoma

Cited by 2 publications

References 50 publications

AI-Assisted chemical probe discovery for the understudied Calcium-Calmodulin Dependent Kinase, PNCK

AI-Assisted chemical probe discovery for the understudied Calcium-Calmodulin Dependent Kinase, PNCK

Regulation of ErbB Receptors by the Ca2+ Sensor Protein Calmodulin in Cancer

Contact Info

Product

Resources

About