III Convegno Annuale "L'era delle 3R: modelli in silico, in vitro e in vivo per promuovere la ricerca traslazionale"

SPILLOproject contribution:

VIDEO POSTER PRESENTATION

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

Presenting Author: Omar Ben Mariem^a,b,*

Authors: A. Malacrida^d , M. Rivara^c , Omar Ben Mariem^a,b,* , A. Di Domizio^a,b,*, G. Cislaghi^a , M. Miloso^d , V. Zuliani^c , G. Nicolini<sup>d

a</sup> SPILLOproject, Paderno Dugnano (MI), Italy
^b Dept. of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milano, Milano, Italy
^c Food and Drug Department, University of Parma, Parma, Italy
^d Experimental Neurology Unit and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy

* Corresponding Author: omar.benmariem@spilloproject.com

Topic: In silico models

The innovative in silico technologies developed at SPILLOproject ^[1], e.g., the SPILLO potential binding sites searcher (SPILLO-PBSS) software ^[3], allow to identify targets and off-targets of any small molecule on a multiple-organism proteome-wide scale, and to perform an accurate multilevel cross-organism transferability analysis (MCOTA) ^[4] 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 first-line treatment for GBM ^[2]. 

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References:

[1] SPILLOproject. www.spilloproject.com

[2] Malacrida A. et al., 3D proteome-wide scale screening and activity evaluation of a new ALKBH5 inhibitor in U87 glioblastoma cell line. Bioorg. & Med. Chem. (2019). doi: 10.1016/j.bmc.2019.115300

[3] Di Domizio A. et al., SPILLO-PBSS: Detecting hidden binding sites within protein 3D-structures through a flexible structure-based approach. J. Comput. Chem. (2014). doi: 10.1002/jcc.23714

[4] Di Domizio A. 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). doi: 10.1021/acs.jmedchem.0c02039