Synthesis of an aryloxy oxo pyrimidinone library that displays ALK-selective inhibition

P Jake Slavish; Jeanine E Price; Qin Jiang; Xiaoli Cui; Stephan W Morris; Thomas R Webb

doi:10.1016/j.bmcl.2011.05.103

Synthesis of an aryloxy oxo pyrimidinone library that displays ALK-selective inhibition

Bioorg Med Chem Lett. 2011 Aug 1;21(15):4592-6. doi: 10.1016/j.bmcl.2011.05.103. Epub 2011 Jun 12.

Authors

P Jake Slavish¹, Jeanine E Price, Qin Jiang, Xiaoli Cui, Stephan W Morris, Thomas R Webb

Affiliation

¹ Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, United States.

PMID: 21708465
DOI: 10.1016/j.bmcl.2011.05.103

Abstract

We report the synthesis of a pyrimidinone library that targets anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase. This library was generated in three steps from a versatile commercially available starting material. Some compounds within this library showed single digit micromolar inhibition of ALK in vitro, while showing minimal inhibition of other homologous insulin receptor family kinases including the human insulin receptor kinase (IRK), at the highest concentrations investigated. We also present initial ALK structure-activity relationships for this library.

Publication types

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

MeSH terms

Anaplastic Lymphoma Kinase
Antigens, CD / metabolism
Humans
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry*
Pyrimidinones / pharmacology
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Receptor, Insulin / antagonists & inhibitors
Receptor, Insulin / metabolism
Structure-Activity Relationship

Substances

Antigens, CD
Protein Kinase Inhibitors
Pyrimidinones
ALK protein, human
Anaplastic Lymphoma Kinase
INSR protein, human
Receptor Protein-Tyrosine Kinases
Receptor, Insulin