Download MendeleyPseudo-Cyclization through Intramolecular Hydrogen Bond Enables Discovery of Pyridine Substituted Pyrimidines as New Mer Kinase Inhibitors.
Zhang, W., Zhang, D., Stashko, M.A., Deryckere, D., Hunter, D., Kireev, D., Miley, M.J., Cummings, C., Lee, M., Norris-Drouin, J., Stewart, W.M., Sather, S., Zhou, Y., Kirkpatrick, G., Machius, M., Janzen, W.P., Earp, H.S., Graham, D.K., Frye, S.V., Wang, X.(2013) J Med Chem 56: 9683-9692
- PubMed: 24195762
- DOI: https://doi.org/10.1021/jm401387j
- Primary Citation of Related Structures:
4M3Q - PubMed Abstract:
Abnormal activation or overexpression of Mer receptor tyrosine kinase has been implicated in survival signaling and chemoresistance in many human cancers. Consequently, Mer is a promising novel cancer therapeutic target. A structure-based drug design approach using a pseudo-ring replacement strategy was developed and validated to discover a new family of pyridinepyrimidine analogues as potent Mer inhibitors. Through SAR studies, 10 (UNC2250) was identified as the lead compound for further investigation based on high selectivity against other kinases and good pharmacokinetic properties. When applied to live cells, 10 inhibited steady-state phosphorylation of endogenous Mer with an IC50 of 9.8 nM and blocked ligand-stimulated activation of a chimeric EGFR-Mer protein. Treatment with 10 also resulted in decreased colony-forming potential in rhabdoid and NSCLC tumor cells, thereby demonstrating functional antitumor activity. The results provide a rationale for further investigation of this compound for therapeutic application in patients with cancer.
Organizational Affiliation:
Center for Integrative Chemical Biology and Drug Discovery and ‡Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
