Small Molecule Inhibitors of Protein Kinase D: Early Development, Current Approaches, and Future Directions

Abstract

Now entering its fourth decade, research on the biological function, small molecule inhibition, and disease relevance of the three known isoforms of protein kinase D, PKD1, PKD2, and PKD3, has entered a mature development stage. This miniperspective focuses on the medicinal chemistry that provided a structurally diverse set of mainly active site inhibitors, which, for a brief time period, moved through preclinical development stages but have yet to be tested in clinical trials. In particular, between 2006 and 2012, a rapid expansion of synthetic efforts led to several moderately to highly PKD-selective chemotypes but did not yet achieve PKD subtype selectivity or resolve general toxicity and pharmacokinetic challenges. In addition to cancer, other unresolved medical needs in cardiovascular, inflammatory, and metabolic diseases would, however, benefit from a renewed focus on potent and selective PKD modulators.

Discovery of C-5 Pyrazole-Substituted Pyrrolopyridine Derivatives as Potent and Selective Inhibitors for Janus Kinase 1

“…In this in vitro panel assay, 12b showed strong interaction with PKD2, HPK1, and AurB and has an excellent selectivity profile over other kinases. Interestingly, PKD2, HPK1, and AurB are considered as promising targets for tumor immunotherapy. This finding indicated that 12b has the potential to be a multitargeted receptor lead compound.…”