Abstract
Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / therapeutic use*
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Cell Line, Tumor
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Dogs
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Female
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Humans
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Macaca fascicularis
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Madin Darby Canine Kidney Cells
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Male
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Mice, SCID
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Molecular Structure
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Multiple Myeloma / drug therapy*
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / therapeutic use*
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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-pim-1 / metabolism
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Pyrazoles / chemical synthesis
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Pyrazoles / metabolism
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Pyrazoles / therapeutic use*
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyrazoles
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PIM1 protein, human
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Proto-Oncogene Proteins c-pim-1