Discovery of Potent Bruton's Tyrosine Kinase Inhibitors Using Ligand Based Modeling.
BACKGROUND
Bruton's Tyrosine Kinase (BTK) is a one of the Tec tyrosine kinase family. It has an essential role in B-cell development and function. Activation of BTK has been associated with the pathogenesis of many types of lymphomas and leukemia, and involved in non-life threatening autoimmune diseases.


OBJECTIVE
In this study, exhaustive pharmacophore modeling was combined with QSAR analyses to examine the structural requirements for anti-BTK activities.


METHODS
Genetic function algorithm (GFA) was coupled with multiple linear regression (MLR) analysis to select the best combinations of physicochemical descriptors and pharmacophoric hypothesis capable of generating predictive and self-consistent QSAR models. The optimum pharmacophores were decorated with exclusion volumes to improve their receiver operating characteristic (ROC) curve properties. The best predictive QSAR model and its corresponding pharmacophore models were validated by discovering of novel promising BTK inhibitors retrieved from the National Cancer Institute (NCI) database.


RESULTS
Several potent hits exhibited anti-proliferative activities on U-937 cell-line in low micromolar IC50, and one active compound showed nontoxic activities on normal fibroblast cell line.


CONCLUSIONS
Our efforts culminated in the identification of potent BTK ligands having desired inhibitory activities and structurally distinct from known active reference compounds (i.e., training compounds) and represent new chemotypes.
Wafa A
WA
Mera
Malek
M
Alzihlif
Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942,Jordan.
Mutasem O
MO
Taha
Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942,Jordan.
Mohammad A
MA
Khanfar
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000465:Algorithms; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology; D008024:Ligands; D016014:Linear Models; D008223:Lymphoma / Q000188:drug therapy / Q000201:enzymology; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve
D000970:Antineoplastic Agents; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human