One of the main reasons for loss of sensitivity to hormonetherapy in breast cancer patients is the development of Acquired drugresistance. Mechanically, the abnormal activation of the Akt / mTOR signalingpathway and the overexpression of LMTK3, are the main factors involved in the generatingof this résistance.These factors constitute therefore a very interesting fieldof research, and approaches aiming to target this mechanism by abrogatingresistance induced by Akt and lmtk3 are therefore of great relevance oftreatements breast cancerLemur tyrosine kinase-3 (LMTK3), a member of theserine-threonine tyrosine kinase family,plays a central role in endocrine resistance ,It has been considered as a promising therapeutic target in the breast cancertreatment.Indeed, this protein is incriminated in the induction ofresistance to hormonal treatment by two mechanisms. First, it regulates of ESR1 transcriptional activation byinhibiting PKC, which leads to a decrease of phosphorylated AKT (Ser473), responsiblefor the FOXO3 stabilization which allows the increase of the Er? transcriptionalactivity.
Secondly, it allows the ER? protein direct phosphorylation, protectit from protease degradation mediated by ubiquitin(Ub). Thus, in front of resistance to endocrine treatment, inhibitionof LMTK3 resulted in re-sensitization to treatment, and increased AKTphosphorylation and other unidentified PKC targetsThe Akt1 is one of the 3 closely related serine /threonine-protein kinases (AKT1, AKT2 and AKT3) The aberrant expression of LMTK3 and AKT has been observedin several types of humans cancer, including breast cancer, lung cancer (anaplasticsmall cell), bladder cancerHowever, recent studies have demonstrated that inhibition ofLMTK3, (3)and pathway (Akt and / or mTOR) deletion , restore sensitivity to anti-estrogentreatment in breast cancer cells(13),These are, therefore, two proteins that play a critical rolein the cancer therapy development; (14) (15) (16), these molecules have characteristics necessary for design of effective andreliable small drug molecule.The identification of lead compounds with a pharmacologicalactivity against a biological target and the optimization of their propertiesare the starting points in the early stages of drug discovery. This discoveryitself is a complex process that would take 12 to 15 years and cost more than $ 1 billion.
The treatment effectiveness is the prerogative of either asingle anticancer molecule with a specific target, or the combination ofseveral molecules thus aiming different therapeutic targets.Consequently, the pharmaceutical industry adopted,firstly, the virtual screening of chemicals products against a relevant therapeutic target as ameans of identifying new lead compounds, and secondly the computational methods(in silico) in development process of these compounds before the preclinicalstage, particularly in the physicochemical, pharmacodynamic and pharmacokineticproperties study.Quantitative structure-activity relationship (QSAR) models,are quantitative regression methods which enable to link the chemical structureto the biological activity. They have extensively been applied in severalscientific disciplines:chemistry, biology and toxicology(17) (18).
QSAR models are considered a scientifically credible tool for predicting andclassifying biological activities of untested chemicals. This tool has become an essential method of discovery andleading edge optimization to direct development (19) (20)in the pharmaceutical industry.