Warnault P.,University of Nice Sophia Antipolis |
Yasri A.,OriBasePharma |
Coisy-Quivy M.,OriBasePharma |
Cheve G.,OriBasePharma |
And 3 more authors.
Current Medicinal Chemistry | Year: 2013
The tyrosine kinase epidermal growth factor receptor (EGFR) has emerged in recent years as a key and validated target of targeted therapies for solid tumors. It plays a central role in oncology since it is involved in many steps of tumor progression such as proliferation, angiogenesis, invasiveness, decreased apoptosis, and loss of differentiation. Recent advances in targeted therapies have demonstrated that tyrosine kinase inhibitors (TKIs), have provided a marked benefit to subsets of patients whose tumors harbor specific genetic abnormalities. However, resistance phenomenon appears rapidly and patients with EGFR mutations acquire resistance to TKI inhibitors decreasing therefore the median time to disease progression to few months. Several strategies were envisioned to overcome this resistance, such as dual-target inhibitors, multitarget and combined therapy. This review summarizes recent advances in TKIs development with special focus on rational strategies for the design of potent EGFR inhibitors including molecular modeling studies based on crystallographic data. Such advances open the way for new research possibilities in modern medicinal chemistry combined to structure-based drug design. © 2013 Bentham Science Publishers.
PubMed | Mohammed V University and OribasePharma
Type: | Journal: OncoTargets and therapy | Year: 2016
The discovery of clinically relevant inhibitors of mammalian target of rapamycin (mTOR) for anticancer therapy has proved to be a challenging task. The quantitative structure-activity relationship (QSAR) approach is a very useful and widespread technique for ligand-based drug design, which can be used to identify novel and potent mTOR inhibitors. In this study, we performed two-dimensional QSAR tests, and molecular docking validation tests of a series of mTOR ATP-competitive inhibitors to elucidate their structural properties associated with their activity. The QSAR tests were performed using partial least square method with a correlation coefficient of