Discovery of novel 3,5-disubstituted indole derivatives as potent inhibitors of Pim-1, Pim-2, and Pim-3 protein kinases

Gisele A Nishiguchi; Gordana Atallah; Cornelia Bellamacina; Matthew T Burger; Yu Ding; Paul H Feucht; Pablo D Garcia; Wooseok Han; Liana Klivansky; Mika Lindvall

doi:10.1016/j.bmcl.2011.08.105

Discovery of novel 3,5-disubstituted indole derivatives as potent inhibitors of Pim-1, Pim-2, and Pim-3 protein kinases

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6366-9. doi: 10.1016/j.bmcl.2011.08.105. Epub 2011 Sep 10.

Authors

Gisele A Nishiguchi¹, Gordana Atallah, Cornelia Bellamacina, Matthew T Burger, Yu Ding, Paul H Feucht, Pablo D Garcia, Wooseok Han, Liana Klivansky, Mika Lindvall

Affiliation

¹ Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes of BioMedical Research, Emeryville, CA 94608, USA. gisele.nishiguchi@novartis.com

PMID: 21945284
DOI: 10.1016/j.bmcl.2011.08.105

Abstract

A series of novel 3,5-disubstituted indole derivatives as potent and selective inhibitors of all three members of the Pim kinase family is described. High throughput screen identified a pan-Pim kinase inhibitor with a promiscuous scaffold. Guided by structure-based drug design, SAR of the series afforded a highly selective indole chemotype that was further developed into a potent set of compounds against Pim-1, 2, and 3 (Pim-1 and Pim-3: IC(50)≤2nM and Pim-2: IC(50)≤100nM).

MeSH terms

Drug Discovery*
Indoles / chemistry*
Indoles / pharmacology*
Inhibitory Concentration 50
Models, Molecular
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Kinases / drug effects*
Structure-Activity Relationship

Substances

Indoles
Protein Kinase Inhibitors
Protein Kinases