Innovative 3D proteome-wide scale identification of ALKBH5 target for MV1035 small molecule able to reduce migration and invasiveness in U87 glioblastoma cell lines by SPILLO-PBSS


https://doi.org/10.4081/bse.178
Vol. 2 No. 1 (2021)
Published: 29 September 2021
Targets and off-targets identification, ALKBH5, ALKBH2, animal testing reduction, multilevel cross-organism transferability analysis (MCOTA)
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Authors

  • Alessio Malacrida Experimental Neurology Unit and Milan Center for Neuroscience, University of Milano-Bicocca, Monza (MB), Italy.
  • Mirko Rivara Food and Drug Department, University of Parma, Parma, Italy.
  • Omar Ben Mariem
    omar.benmariem@spilloproject.com
    SPILLOproject, Paderno Dugnano (MI, www.spilloproject.com); Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milano, Milano (MI), Italy.
  • Alessandro Di Domizio SPILLOproject, Paderno Dugnano (MI, www.spilloproject.com); Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milano, Milano (MI), Italy.
  • Giacomo Cislaghi SPILLOproject, Paderno Dugnano (MI, www.spilloproject.com), Italy.
  • Mariarosaria Miloso Experimental Neurology Unit and Milan Center for Neuroscience, University of Milano-Bicocca, Monza (MB), Italy.
  • Valentina Zuliani Food and Drug Department, University of Parma, Parma, Italy.
  • Gabriella Nicolini Experimental Neurology Unit and Milan Center for Neuroscience, University of Milano-Bicocca, Monza (MB), Italy.

The innovative in silico technologies developed at SPILLOproject,1 e.g., the SPILLO potential binding sites searcher (SPILLO-PBSS) software,2,3 allow to identify targets and off-targets of any small molecule on a multiple-organism proteomewide scale, and to perform an accurate multilevel cross-organism transferability analysis (MCOTA) aimed at rationalising animal testing. SPILLO-PBSS has been successfully used in several research projects, such as a study in which a compound (MV1035) was found to reduce migration and invasiveness in U87 glioblastoma (GBM) cell lines: the human structural proteome was analyzed and the RNA demethylase ALKBH5 has been identified as a target responsible for the observed effects (target experimentally validated). Another top-ranked target identified by SPILLO-PBSS, the DNA repair protein AlkB homolog 2 (ALKBH2), abundantly expressed in GBM cell lines, resulted particularly interesting for its pivotal role in the onset of resistance to Temozolomide (TMZ), the standard firstline treatment for GBM.2


1. SPILLOproject. Available from: www.spilloproject.com
2. Malacrida A, Rivara M, Di Domizio A, Cislaghi G, Miloso M, Zuliani V, Nicolini G. 3D proteome-wide scale screening and activity evaluation of a new ALKBH5 inhibitor in U87 glioblastoma cell line. Bioorg Med Chem 2020;28:115300.
3. Di Domizio A, Vitriolo A, Vistoli G, Pedretti A. SPILLO-PBSS: detecting hidden binding sites within protein 3D-structures through a flexible structure-based approach. J Comput Chem 2014;35:2005-17.
4. Giatti S, Di Domizio A, Diviccaro S, et al. Three-dimensional proteome-wide scale screening for the 5-alpha reductase inhibitor finasteride: identification of a novel off-target. J Med Chem 2021;64:4553-66.
Malacrida, A., Rivara, M., Mariem, O. B., Di Domizio, A. ., Cislaghi, G., Miloso, M., Zuliani, V., & Nicolini, G. (2021). Innovative 3D proteome-wide scale identification of ALKBH5 target for MV1035 small molecule able to reduce migration and invasiveness in U87 glioblastoma cell lines by SPILLO-PBSS. Biomedical Science and Engineering, 2(1). https://doi.org/10.4081/bse.178

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