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@ARTICLE{Wittenburg:302999,
      author       = {S. Wittenburg and M. R. Zuleeg and K. Peter and P.
                      Lemnitzer and R. Voget and A. Bricelj and M. Gobec and N.
                      Dierlamm and M. B. Braun and T. M. Geiger and C. Heim and A.
                      Stakemeier and K. G. Wagner and R. P. Nowak and M. D.
                      Hartmann and I. Sosič and M. Gütschow and J. Krönke$^*$
                      and C. Steinebach},
      title        = {{E}nhancing {S}olubility in {VHL}-{B}ased {PROTAC}s:
                      {O}ptimized {USP}7 {D}egraders for {I}mproved
                      {D}evelopability.},
      journal      = {Journal of medicinal chemistry},
      volume       = {68},
      number       = {15},
      issn         = {0095-9065},
      address      = {Washington, DC},
      publisher    = {ACS},
      reportid     = {DKFZ-2025-01446},
      pages        = {15711-15737},
      year         = {2025},
      note         = {2025 Aug 14;68(15):15711-15737},
      abstract     = {Limited aqueous solubility, high total polar surface area
                      (TPSA), and high hydrogen-bond donor (HBD) counts have
                      hampered the clinical development of VHL-based
                      proteolysis-targeting chimeras (PROTACs). This study
                      explores strategies to enhance the physicochemical
                      properties of VHL-recruiting USP7 degraders. By adjusting
                      lipophilicity, HBD count, and TPSA, we created degraders
                      with improved solubility while maintaining their USP7
                      degradation capability. Structural modifications at the VHL
                      ligand included a constrained six-membered ring in the
                      peptidic scaffold and the addition of solubilizing groups.
                      These changes enhanced aqueous solubility without
                      compromising degradation performance. A key example is
                      PROTAC 40, modified with a dibasic piperazine, which
                      exhibits a 170-fold increase in solubility over its
                      predecessor while retaining strong target selectivity. The
                      findings demonstrate that rational scaffold design can yield
                      solubility-enhanced VHL-based PROTACs with broad potential
                      for drug development. This methodology may also be
                      applicable to other E3 ligases, supporting the development
                      of degraders suitable for in vivo use.},
      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:40673806},
      doi          = {10.1021/acs.jmedchem.5c00718},
      url          = {https://inrepo02.dkfz.de/record/302999},
}