8UVL
Crystal structure of selective IRE1a inhibitor 29 at the enzyme active site
Summary for 8UVL
| Entry DOI | 10.2210/pdb8uvl/pdb |
| Related | 6W39 |
| Descriptor | Serine/threonine-protein kinase/endoribonuclease IRE1, 1,2-ETHANEDIOL, 1-phenyl-N-(2,3,6-trifluoro-4-{[(3M)-3-(2-{[(3R,5R)-5-fluoropiperidin-3-yl]amino}pyrimidin-4-yl)pyridin-2-yl]oxy}phenyl)methanesulfonamide, ... (4 entities in total) |
| Functional Keywords | kinase, cancer, multiple myeloma, selective, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 52457.60 |
| Authors | Kiefer, J.R.,Wallweber, H.A.,Braun, M.-G.,Wei, W.,Jiang, F.,Wang, W.,Rudolph, J.,Ashkenazi, A. (deposition date: 2023-11-03, release date: 2024-05-29, Last modification date: 2024-06-26) |
| Primary citation | Braun, M.G.,Ashkenazi, A.,Beveridge, R.E.,Castanedo, G.,Wallweber, H.A.,Beresini, M.H.,Clark, K.R.,De Bruyn, T.,Fu, L.,Gibbons, P.,Jiang, F.,Kaufman, S.,Kan, D.,Kiefer, J.R.,Leclerc, J.P.,Lemire, A.,Ly, C.,Segal, E.,Sims, J.,Wang, W.,Wei, W.,Zhao, L.,Schwarz, J.B.,Rudolph, J. Discovery of Potent, Selective, and Orally Available IRE1 alpha Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model. J.Med.Chem., 67:8708-8729, 2024 Cited by PubMed 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, , that was well tolerated following multiday oral administration of doses up to 500 mg/kg. demonstrated comparable pharmacodynamic effects to induced IRE1 knockdown as measured by XBP1s levels in a multiple myeloma model (KMS-11). PubMed: 38748820DOI: 10.1021/acs.jmedchem.3c02425 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.43 Å) |
Structure validation
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