8uvl
Crystal structure of selective IRE1a inhibitor 29 at the enzyme active site
Structural highlights
FunctionERN1_HUMAN Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto-activation. The active endoribonuclease domain splices XBP1 mRNA to generate a new C-terminus, converting it into a potent unfolded-protein response transcriptional activator and triggering growth arrest and apoptosis.[1] [2] [3] [UniProtKB:Q9EQY0] Publication Abstract from PubMedThe lack of selective and safe in vivo IRE1alpha tool molecules has limited the evaluation of IRE1alpha 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). Discovery of Potent, Selective, and Orally Available IRE1alpha Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model.,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, Rudolph J J Med Chem. 2024 May 15. doi: 10.1021/acs.jmedchem.3c02425. PMID:38748820[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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