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@ARTICLE{Bhatia:907780,
      author       = {Bhatia, Sanil and Spanier, Lukas and Bickel, David and
                      Dienstbier, Niklas and Woloschin, Vitalij and Vogt, Melina
                      and Pols, Henrik and Lungerich, Beate and Reiners, Jens and
                      Aghaallaei, Narges and Diedrich, Daniela and Frieg, Benedikt
                      and Schliehe-Diecks, Julian and Bopp, Bertan and Lang,
                      Franziska and Gopalswamy, Mohanraj and Loschwitz, Jennifer
                      and Bajohgli, Baubak and Skokowa, Julia and Borkhardt, Arndt
                      and Hauer, Julia and Hansen, Finn K. and Smits, Sander H. J.
                      and Jose, Joachim and Gohlke, Holger and Kurz, Thomas},
      title        = {{D}evelopment of a {F}irst-in-{C}lass {S}mall-{M}olecule
                      {I}nhibitor of the {C}-{T}erminal {H}sp90 {D}imerization},
      journal      = {ACS central science},
      volume       = {8},
      number       = {5},
      issn         = {2374-7943},
      address      = {Washington, DC},
      publisher    = {ACS Publ.},
      reportid     = {FZJ-2022-02209},
      pages        = {636–655},
      year         = {2022},
      abstract     = {Heat shock proteins 90 (Hsp90) are promising therapeutic
                      targets due to their involvement in stabilizing several
                      aberrantly expressed oncoproteins. In cancerous cells, Hsp90
                      expression is elevated, thereby exerting antiapoptotic
                      effects, which is essential for the malignant transformation
                      and tumor progression. Most of the Hsp90 inhibitors (Hsp90i)
                      under investigation target the ATP binding site in the
                      N-terminal domain of Hsp90. However, adverse effects,
                      including induction of the prosurvival resistance mechanism
                      (heat shock response or HSR) and associated dose-limiting
                      toxicity, have so far precluded their clinical approval. In
                      contrast, modulators that interfere with the C-terminal
                      domain (CTD) of Hsp90 do not inflict HSR. Since the CTD
                      dimerization of Hsp90 is essential for its chaperone
                      activity, interfering with the dimerization process by
                      small-molecule protein–protein interaction inhibitors is a
                      promising strategy for anticancer drug research. We have
                      developed a first-in-class small-molecule inhibitor (5b)
                      targeting the Hsp90 CTD dimerization interface, based on a
                      tripyrimidonamide scaffold through structure-based molecular
                      design, chemical synthesis, binding mode model prediction,
                      assessment of the biochemical affinity, and efficacy against
                      therapy-resistant leukemia cells. 5b reduces
                      xenotransplantation of leukemia cells in zebrafish models
                      and induces apoptosis in BCR-ABL1+ (T315I) tyrosine kinase
                      inhibitor-resistant leukemia cells, without inducing HSR.},
      cin          = {IBG-4 / JSC / NIC / IBI-7},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IBG-4-20200403 / I:(DE-Juel1)JSC-20090406 /
                      I:(DE-Juel1)NIC-20090406 / I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5111 - Domain-Specific Simulation $\&$ Data Life Cycle Labs
                      (SDLs) and Research Groups (POF4-511) / 2171 - Biological
                      and environmental resources for sustainable use (POF4-217) /
                      Forschergruppe Gohlke $(hkf7_20200501)$ / 5241 - Molecular
                      Information Processing in Cellular Systems (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5111 / G:(DE-HGF)POF4-2171 /
                      $G:(DE-Juel1)hkf7_20200501$ / G:(DE-HGF)POF4-5241},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {35647282},
      UT           = {WOS:000806002600015},
      doi          = {10.1021/acscentsci.2c00013},
      url          = {https://juser.fz-juelich.de/record/907780},
}