1. Discovery of Potent, Selective, and Orally Available IRE1α Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model.
- Author
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Braun MG, Ashkenazi A, Beveridge RE, Castanedo G, Wallweber HA, Beresini MH, Clark KR, De Bruyn T, Fu L, Gibbons P, Jiang F, Kaufman S, Kan D, Kiefer JR, Leclerc JP, Lemire A, Ly C, Segal E, Sims J, Wang W, Wei W, Zhao L, Schwarz JB, and Rudolph J
- Subjects
- Humans, Administration, Oral, Animals, Drug Discovery, Mice, Cell Line, Tumor, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Rats, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors pharmacokinetics, Gene Knockdown Techniques, X-Box Binding Protein 1 metabolism, X-Box Binding Protein 1 genetics, Multiple Myeloma drug therapy, Multiple Myeloma pathology, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases metabolism, Endoribonucleases antagonists & inhibitors, Endoribonucleases metabolism
- 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).
- Published
- 2024
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