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@ARTICLE{Zhou:278402,
      author       = {M. Zhou and J. C. Boulos and E. A. Omer and S. M.
                      Klauck$^*$ and T. Efferth},
      title        = {{M}odes of {A}ction of a {N}ovel c-{MYC} {I}nhibiting
                      1,2,4-{O}xadiazole {D}erivative in {L}eukemia and {B}reast
                      {C}ancer {C}ells.},
      journal      = {Molecules},
      volume       = {28},
      number       = {15},
      issn         = {1420-3049},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2023-01636},
      pages        = {5658},
      year         = {2023},
      abstract     = {The c-MYC oncogene regulates multiple cellular activities
                      and is a potent driver of many highly aggressive human
                      cancers, such as leukemia and triple-negative breast cancer.
                      The oxadiazole class of compounds has gained increasing
                      interest for its anticancer activities. The aim of this
                      study was to investigate the molecular modes of action of a
                      1,2,4-oxadiazole derivative (ZINC15675948) as a c-MYC
                      inhibitor. ZINC15675948 displayed profound cytotoxicity at
                      the nanomolar range in CCRF-CEM leukemia and
                      MDA-MB-231-pcDNA3 breast cancer cells. Multidrug-resistant
                      sublines thereof (i.e., CEM/ADR5000 and MDA-MB-231-BCRP)
                      were moderately cross-resistant to this compound (<10-fold).
                      Molecular docking and microscale thermophoresis revealed a
                      strong binding of ZINC15675948 to c-MYC by interacting close
                      to the c-MYC/MAX interface. A c-MYC reporter assay
                      demonstrated that ZINC15675948 inhibited c-MYC activity.
                      Western blotting and qRT-PCR showed that c-MYC expression
                      was downregulated by ZINC15675948. Applying microarray
                      hybridization and signaling pathway analyses, ZINC15675948
                      affected signaling routes downstream of c-MYC in both
                      leukemia and breast cancer cells as demonstrated by the
                      induction of DNA damage using single cell gel
                      electrophoresis (alkaline comet assay) and induction of
                      apoptosis using flow cytometry. ZINC15675948 also caused
                      G2/M phase and S phase arrest in CCRF-CEM cells and
                      MDA-MB-231-pcDNA3 cells, respectively, accompanied by the
                      downregulation of CDK1 and p-CDK2 expression using western
                      blotting. Autophagy induction was observed in CCRF-CEM cells
                      but not MDA-MB-231-pcDNA3 cells. Furthermore,
                      microarray-based mRNA expression profiling indicated that
                      ZINC15675948 may target c-MYC-regulated ubiquitination,
                      since the novel ubiquitin ligase (ELL2) was upregulated in
                      the absence of c-MYC expression. We propose that
                      ZINC15675948 is a promising natural product-derived compound
                      targeting c-MYC in c-MYC-driven cancers through DNA damage,
                      cell cycle arrest, and apoptosis.},
      keywords     = {1,2,4-oxadiazole (Other) / c-MYC inhibitor (Other) /
                      leukemia (Other) / natural product derivative (Other) /
                      oncogenes (Other) / triple-negative breast cancer (Other)},
      cin          = {B063 / HD01},
      ddc          = {540},
      cid          = {I:(DE-He78)B063-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37570631},
      pmc          = {pmc:PMC10419799},
      doi          = {10.3390/molecules28155658},
      url          = {https://inrepo02.dkfz.de/record/278402},
}