ABSTRACT
Fyn is a member of the Src-family of nonreceptor protein-tyrosine kinases. Its abnormal activity has been shown to be related to various human cancers as well as to severe pathologies, such as Alzheimer's and Parkinson's diseases. Herein, a structure-based drug design protocol was employed aimed at identifying novel Fyn inhibitors. Two hits from commercial sources (1, 2) were found active against Fyn with K(i) of about 2 µM, while derivative 4a, derived from our internal library, showed a K(i) of 0.9 µM. A hit-to-lead optimization effort was then initiated on derivative 4a to improve its potency. Slightly modifications rapidly determine an increase in the binding affinity, with the best inhibitors 4c and 4d having K(i)s of 70 and 95 nM, respectively. Both compounds were found able to inhibit the phosphorylation of the protein Tau in an Alzheimer's model cell line and showed antiproliferative activities against different cancer cell lines.
Subject(s)
Adenosine Triphosphate/metabolism , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-fyn/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Tauopathies/drug therapy , Antineoplastic Agents/chemistry , Binding Sites , Cell Proliferation/drug effects , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Neoplasms/enzymology , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-fyn/metabolism , Pyrazoles/chemistry , Pyrimidines/chemistry , Signal Transduction/drug effects , Structure-Activity Relationship , Tauopathies/enzymology , Tumor Cells, CulturedABSTRACT
INTRODUCTION: Breakpoint cluster region Abelson (Bcr-Abl) tyrosine kinase (TK) is a constitutively activated cytoplasmic TK and is the underlying cause of chronic myeloid leukemia (CML). To date, imatinib represents the frontline treatment for CML therapy. The development of resistance has prompted the search for novel Bcr-Abl inhibitors. AREAS COVERED: This review presents a short overview of drugs already approved for CML therapy and of the compounds that are in clinical trials. The body of the article deals with Bcr-Abl inhibitors patented since 2008, focusing on their chemical features. EXPERT OPINION: The search for Bcr-Abl inhibitors is very active. We believe that a number of patented compounds could enter clinical trials and some could be approved for CML therapy in the next few years. Overall, Bcr-Abl inhibitors constitute a very appealing research field that can be expected to expand further.
