8ou3

Cereblon isoform 4 in complex with novel Benzamide-Type Cereblon Binder 8d

spinqualitylabelsall models 8ou3, resolution 1.47Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8ou3 is a 3 chain structure with sequence from Magnetospirillum gryphiswaldense. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.47Å Ligands: EF2, PO4, W1T, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A4TVL0_9PROT Publication Abstract from PubMed Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds. Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs.,Steinebach C, Bricelj A, Murgai A, Sosic I, Bischof L, Ng YLD, Heim C, Maiwald S, Proj M, Voget R, Feller F, Kosmrlj J, Sapozhnikova V, Schmidt A, Zuleeg MR, Lemnitzer P, Mertins P, Hansen FK, Gutschow M, Kronke J, Hartmann MD J Med Chem. 2023 Nov 9;66(21):14513-14543. doi: 10.1021/acs.jmedchem.3c00851. , Epub 2023 Oct 30. PMID:37902300 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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