AI-Assisted Chemical Probe Discovery for the Understudied Calcium-Calmodulin Dependent Kinase, PNCK

Abstract

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 first described inhibitor hit series for PNCK that will serve as the starting point for future medicinal chemistry efforts for hit-to-lead optimization of potent chemical probes.

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

“…Results from analysis of the TCGA RCC cohort, which demonstrate a statistically significant correlation between PNCK expression, TNM stage, and disease-specific survival Studies aimed at developing in vivo genetic models of PNCK silencing and at identifying novel small molecule chemical inhibitors of PNCK are currently underway. 48 …”