Abstract
The lack of selective and safe in vivo IRE1α tool molecules has limited the evaluation of IRE1α as a viable target to treat multiple myeloma. Focus on improving the physicochemical properties of a literature compound by decreasing lipophilicity, molecular weight, and basicity allowed the discovery of a novel series with a favorable in vitro safety profile and good oral exposure. These efforts culminated in the identification of a potent and selective in vivo tool compound, G-5758, that was well tolerated following multiday oral administration of doses up to 500 mg/kg. G-5758 demonstrated comparable pharmacodynamic effects to induced IRE1 knockdown as measured by XBP1s levels in a multiple myeloma model (KMS-11).
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Cell Line, Tumor
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Drug Discovery
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Endoribonucleases* / antagonists & inhibitors
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Endoribonucleases* / metabolism
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Gene Knockdown Techniques
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Humans
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Mice
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Multiple Myeloma* / drug therapy
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Multiple Myeloma* / pathology
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Protein Serine-Threonine Kinases* / antagonists & inhibitors
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Protein Serine-Threonine Kinases* / metabolism
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Rats
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Structure-Activity Relationship
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X-Box Binding Protein 1 / genetics
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X-Box Binding Protein 1 / metabolism
Substances
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Protein Serine-Threonine Kinases
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ERN1 protein, human
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Endoribonucleases
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Antineoplastic Agents
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Protein Kinase Inhibitors
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X-Box Binding Protein 1