title: Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design.
abstract: 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.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. wang.xiaojing@gene.com
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.forename: Steven
authors.initials: S
authors.lastname: Magnuson
authors.forename: Rich
authors.initials: R
authors.lastname: Pastor
authors.forename: Eric
authors.initials: E
authors.lastname: Fan
authors.forename: Huiyong
authors.initials: H
authors.lastname: Hu
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
authors.forename: Jeremy
authors.initials: J
authors.lastname: Murray
authors.forename: Micah
authors.initials: M
authors.lastname: Steffek
authors.forename: Heidi
authors.initials: H
authors.lastname: Wallweber
authors.forename: John
authors.initials: J
authors.lastname: Moffat
authors.forename: Jason
authors.initials: J
authors.lastname: Drummond
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.forename: Eric
authors.initials: E
authors.lastname: Harstad
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Ebens
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D051379:Mice; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C527752:pyrazolo(1,5-a)pyrimidine; D051573:Proto-Oncogene Proteins c-pim-1