The design, synthesis, and biological evaluation of PIM kinase inhibitors

Amy Lew Tsuhako; David S Brown; Elena S Koltun; Naing Aay; Arlyn Arcalas; Vicky Chan; Hongwang Du; Stefan Engst; Maurizio Franzini; Adam Galan; Ping Huang; Stuart Johnston; Brian Kane; Moon H Kim; A Douglas Laird; Rui Lin; Lillian Mock; Iris Ngan; Michael Pack; Gordon Stott; Thomas J Stout; Peiwen Yu; Cristiana Zaharia; Wentao Zhang; Peiwen Zhou; John M Nuss; Patrick C Kearney; Wei Xu

doi:10.1016/j.bmcl.2012.04.025

The design, synthesis, and biological evaluation of PIM kinase inhibitors

Bioorg Med Chem Lett. 2012 Jun 1;22(11):3732-8. doi: 10.1016/j.bmcl.2012.04.025. Epub 2012 Apr 11.

Affiliation

¹ Exelixis, Department of Drug Discovery, South San Francisco, CA 94080, USA. alew@exelixis.com

PMID: 22542012
DOI: 10.1016/j.bmcl.2012.04.025

Abstract

A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.

MeSH terms

Binding Sites
Computer Simulation
Crystallography, X-Ray
Drug Design*
Furans / chemistry*
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Structure, Tertiary
Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
Proto-Oncogene Proteins c-pim-1 / metabolism
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry*
Pyrimidinones / pharmacology
Structure-Activity Relationship

Substances

Furans
Protein Kinase Inhibitors
Pyrimidinones
Proto-Oncogene Proteins c-pim-1
proto-oncogene proteins pim