ABSTRACT
This paper describes the discovery and design of a novel class of JAK2 inhibitors. Furthermore, we detail the optimization of a screening hit using ligand binding efficiency and log D. These efforts led to the identification of compound 41, which demonstrates in vivo activity in our study.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemistry , Janus Kinase 2/antagonists & inhibitors , Pyridones/chemistry , Animals , Binding Sites , Computer Simulation , Cyclization , Drug Evaluation, Preclinical , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Janus Kinase 2/metabolism , Mice , Mice, Inbred C57BL , Pyridones/chemical synthesis , Pyridones/pharmacology , STAT5 Transcription Factor/metabolism , Structure-Activity RelationshipABSTRACT
Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4+/-0.6 nM, Akt cell potency of 50+/-19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po).