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.

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.

Hematopoietic cell kinase (Hck) is a member of the Src-family of non-receptor tyrosine kinases, which plays many roles in signalling pathways involved in the regulation of cell processes. Hck is expressed in cells of hematopoietic origin, specifically myelomonocytic cells and B lymphocytes. It participates in phagocytosis, adhesion, migration, regulation of protrusion formation on cell membrane, lysosome exocytosis, podosome formation and actin polymerization. More importantly from a medicinal chemistry point of view, high levels of Hck are involved in chronic myeloid leukemia and other hematologic tumors. Furthermore, Hck activity has been associated with virus infections including HIV-1. In particular, Hck is activated by the HIV-1 accessory protein Nef, a multifunctional HIV-1 protein that accelerates progression to AIDS and enhances the infectivity of progeny viruses. Nef binding to Hck leads to kinase activation which is important in AIDS pathogenesis. For these reasons, Hck represents a potentially good therapeutic target for the treatment of both specific cancers and HIV infection. This article summarizes Hck biological activities connected with malignancies and HIV infection, many of which have been only recently reported, and presents an overview of the compounds endowed with Hck inhibitory activity, especially focusing on the medicinal chemistry aspect.