Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design

Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using proper...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 23; no. 11; pp. 3149 - 3153
Main Authors:	Wang, Xiaojing, Magnuson, Steven, Pastor, Rich, Fan, Eric, Hu, Huiyong, Tsui, Vickie, Deng, Wei, Murray, Jeremy, Steffek, Micah, Wallweber, Heidi, Moffat, John, Drummond, Jason, Chan, Grace, Harstad, Eric, Ebens, Allen J.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-06-2013
Subjects:	adenosine triphosphate Animals Binding Sites Cell Line Cell Survival - drug effects chemistry Crystallography, X-Ray Drug Design Drug Evaluation, Preclinical drugs High throughput screening Humans Kinase inhibitor Kinetics Lead optimization Mice myeloma phosphotransferases (kinases) Pim kinases Protein Isoforms - antagonists & inhibitors Protein Isoforms - metabolism 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 Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology pyrimidines Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology screening Structure based drug design Structure-Activity Relationship therapeutics High throughput screening Lead optimization Kinase inhibitor Pim kinases Structure based drug design
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Summary:	Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms.
Bibliography:	http://dx.doi.org/10.1016/j.bmcl.2013.04.020 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.04.020