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@ARTICLE{Dimitrov:276227,
      author       = {T. Dimitrov and A. A. Moschopoulou$^*$ and L. Seidel and T.
                      Kronenberger and M. Kudolo and A. Poso and C. Geibel and P.
                      Wölffing and D. Dauch and L. Zender$^*$ and D. Schollmeyer
                      and J. Bajorath and M. Forster and S. Laufer$^*$},
      title        = {{D}esign and {O}ptimization of {N}ovel {B}enzimidazole- and
                      {I}midazo[4,5-b]pyridine-{B}ased {ATM} {K}inase {I}nhibitors
                      with {S}ubnanomolar {A}ctivities.},
      journal      = {Journal of medicinal chemistry},
      volume       = {66},
      number       = {11},
      issn         = {0095-9065},
      address      = {Washington, DC},
      publisher    = {ACS},
      reportid     = {DKFZ-2023-01036},
      pages        = {7304-7330},
      year         = {2023},
      note         = {2023 Jun 8;66(11):7304-7330},
      abstract     = {The ATM kinase is a promising target in cancer treatment as
                      an important regulator of the cellular response to DNA
                      double-strand breaks. In this work, we present a new class
                      of specific benzimidazole-based ATM inhibitors with
                      picomolar potency against the isolated enzyme and favorable
                      selectivity within relative PIKK and PI3K kinases. We could
                      identify two promising inhibitor subgroups with
                      significantly different physicochemical properties, which we
                      developed simultaneously. These efforts lead to numerous
                      highly active inhibitors with picomolar enzymatic
                      activities. Furthermore, initial low cellular activities on
                      A549 cells could be increased significantly in numerous
                      examples resulting in cellular IC50 values in the
                      subnanomolar range. Further characterization of the highly
                      potent inhibitors 90 und 93 revealed promising
                      pharmacokinetic properties and strong activities in
                      organoids in combination with etoposide. Additionally, 93
                      showed no off-target activities within a
                      kinome-representative mini kinase panel, with favorable
                      selectivities within the PIKK- and PI3K-families.},
      cin          = {TU01},
      ddc          = {610},
      cid          = {I:(DE-He78)TU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37226670},
      doi          = {10.1021/acs.jmedchem.2c02104},
      url          = {https://inrepo02.dkfz.de/record/276227},
}