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Simple Summary: The microtubule cytoskeleton is a key component of the cell and an important target for breast cancer therapy. Microtubule organization and function are tightly regulated by a panel of microtubule-related proteins (MT-Rel) to ensure cellular homeostasis. Deregulation of MT-Rel genes is likely to impact microtubule dynamics and subsequent cell functions. In this study, we evaluate the prognostic value of a panel of 17 MT-Rel genes in breast tumors and the functional consequence of their deregulation using a Systems Biology approach. This study highlights MT-Rel as potential prognostic biomarkers and interesting therapeutical targets to evaluate in breast cancer. A wide panel of microtubule-associated proteins and kinases is involved in coordinated regulation of the microtubule cytoskeleton and may thus represent valuable molecular markers contributing to major cellular pathways deregulated in cancer. We previously identified a panel of 17 microtubule-related (MT-Rel) genes that are differentially expressed in breast tumors showing resistance to taxane-based chemotherapy. In the present study, we evaluated the expression, prognostic value and functional impact of these genes in breast cancer. We show that 14 MT-Rel genes (KIF4A, ASPM, KIF20A, KIF14, TPX2, KIF18B, KIFC1, AURKB, KIF2C, GTSE1, KIF15, KIF11, RACGAP1, STMN1) are up-regulated in breast tumors compared with adjacent normal tissue. Six of them (KIF4A, ASPM, KIF20A, KIF14, TPX2, KIF18B) are overexpressed by more than 10-fold in tumor samples and four of them (KIF11, AURKB, TPX2 and KIFC1) are essential for cell survival. Overexpression of all 14 genes, and underexpression of 3 other MT-Rel genes (MAST4, MAPT and MTUS1) are associated with poor breast cancer patient survival. A Systems Biology approach highlighted three major functional networks connecting the 17 MT-Rel genes and their partners, which are centered on spindle assembly, chromosome segregation and cytokinesis. Our studies identified mitotic Aurora kinases and their substrates as major targets for therapeutic approaches against breast cancer. [ABSTRACT FROM AUTHOR]

Identification of novel chemotypes with biological activity similar to a known active molecule is an important challenge in drug discovery called 'scaffold hopping'. Small‐, medium‐, and large‐step scaffold hopping efforts may lead to increasing degrees of chemical structure novelty with respect to the parent compound. In the present paper, we focus on the problem of large‐step scaffold hopping. We assembled a high quality and well characterized dataset of scaffold hopping examples comprising pairs of active molecules and including a variety of protein targets. This dataset was used to build a benchmark corresponding to the setting of real‐life applications: one active molecule is known, and the second active is searched among a set of decoys chosen in a way to avoid statistical bias. This allowed us to evaluate the performance of computational methods for solving large‐step scaffold hopping problems. In particular, we assessed how difficult these problems are, particularly for classical 2D and 3D ligand‐based methods. We also showed that a machine‐learning chemogenomic algorithm outperforms classical methods and we provided some useful hints for future improvements. [ABSTRACT FROM AUTHOR]