Substituted pteridinones as p90 ribosomal S6 protein kinase (RSK) inhibitors: A structure-activity study

Kimberly A Casalvieri; Christopher J Matheson; Donald S Backos; Philip Reigan

doi:10.1016/j.bmc.2019.115303

Substituted pteridinones as p90 ribosomal S6 protein kinase (RSK) inhibitors: A structure-activity study

Bioorg Med Chem. 2020 Mar 1;28(5):115303. doi: 10.1016/j.bmc.2019.115303. Epub 2020 Jan 12.

Authors

Kimberly A Casalvieri¹, Christopher J Matheson¹, Donald S Backos¹, Philip Reigan²

Affiliations

¹ Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO 80045, USA.
² Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO 80045, USA. Electronic address: philip.reigan@cuanschutz.edu.

PMID: 31982240
DOI: 10.1016/j.bmc.2019.115303

Abstract

The activity of p90 ribosomal S6 kinase 2 (RSK2) has emerged as an attractive target for cancer therapy due to its role in the regulation of diverse cellular processes, such as cell transformation and proliferation. Several pan-RSK inhibitors have been identified with BI-D1870 and the pseudo-analogs LJH685 and LJI308 being the most selective, potent, and frequently used small molecule inhibitors. We designed and synthesized a series of pteridinones and pyrimidines to evaluate the structural features of BI-D1870 that are required for RSK2 inhibition. We have identified inhibitors of RSK2 activity, evaluated their target engagement in cells, and measured their effect on cell viability and cytotoxicity in the MOLM-13 acute myeloid leukemia (AML) cell line. The results of our studies support that RSK2 inhibition can be achieved in MOLM-13 cells without potent cytotoxicity. The structure-activity data from this study will be used as a platform to develop novel RSK2 inhibitors.

Keywords: Cancer; Inhibitor; Kinase; Pteridinones; RSK2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pteridines / chemical synthesis
Pteridines / chemistry
Pteridines / pharmacology*
Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors*
Ribosomal Protein S6 Kinases, 90-kDa / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pteridines
Ribosomal Protein S6 Kinases, 90-kDa