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@ARTICLE{Steinebach:285066,
      author       = {C. Steinebach and A. Bricelj and A. Murgai and I. Sosič
                      and L. Bischof and Y. L. D. Ng and C. Heim and S. Maiwald
                      and M. Proj and R. Voget and F. Feller and J. Košmrlj and
                      V. Sapozhnikova$^*$ and A. Schmidt and M. R. Zuleeg and P.
                      Lemnitzer and P. Mertins and F. K. Hansen and M. Gütschow
                      and J. Krönke and M. D. Hartmann},
      title        = {{L}everaging {L}igand {A}ffinity and {P}roperties:
                      {D}iscovery of {N}ovel {B}enzamide-{T}ype {C}ereblon
                      {B}inders for the {D}esign of {PROTAC}s.},
      journal      = {Journal of medicinal chemistry},
      volume       = {66},
      number       = {21},
      issn         = {0095-9065},
      address      = {Washington, DC},
      publisher    = {ACS},
      reportid     = {DKFZ-2023-02209},
      pages        = {14513-14543},
      year         = {2023},
      note         = {2023 Nov 9;66(21):14513-14543},
      abstract     = {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.},
      cin          = {BE01},
      ddc          = {610},
      cid          = {I:(DE-He78)BE01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37902300},
      doi          = {10.1021/acs.jmedchem.3c00851},
      url          = {https://inrepo02.dkfz.de/record/285066},
}