Novel substituted quinazolines for potent EGFR tyrosine kinase inhibitors.

The type I receptor tyrosine kinases (RTKs) are involved in various aspects of cell growth, survival, and differentiation. Among the known RTKs, the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2) are two widely studied proteins that are prototypic members of the ErbB family which also includes ErbB-3 (Her-3) and ErbB-4 (Her-4). Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate, and squamous carcinoma of head and neck). Disruption of signal transduction of these kinases has been shown to have an antiproliferative effect. Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/Herceptin™ and cetuximab/Erbitux™) directed against the receptor, and synthetic tyrosine kinase inhibitors (gefitinib/Iressa™ and erlotinib/Tarceva™). Since many tumours overexpress ErbB receptors, simultaneous targeting of multiple ErbB receptors therefore becomes a promising approach to cancer treatment. Lapatinib (Tykerb™), a potent dual EGFR/ErbB-2 inhibitor, was approved for the treatment of ErbB-2-positive breast cancer. Despite years of intensive research on EGFR inhibitors, there is a surprising dearth of chemically distinct small inhibitors with a high degree of selectivity. There is also a need for new scaffolds due to the recent finding of EGFR mutations which render the kinase resistant to gefinitib and erlotinib. The structures under study will be quinazolines with different substituents. The structure-activity relationships and biological evaluation of compounds published during the last four years will be reviewed herein.

Human decidual stromal cells express CD34 and STRO-1 and are related to bone marrow stromal precursors.

Decidual stromal cells (DSC) are the main cellular component of the human decidua, but thus far their ascription to a given cell lineage is uncertain. In previous studies, these cells have been isolated and maintained in culture, and their antigen phenotype has been analysed to determine their affiliation. However, the presence in the culture medium of high proportions of fetal calf serum (FCS) may inhibit the expression of some surface antigens. In the present study, we show by flow cytometry that CD34 is rapidly down-regulated in human DSC cultured in RPMI 1640 with 20% FCS. For this reason, we used fibroblast medium, which contains only a small proportion (2%) of FCS, to isolate and culture these cells. Under these conditions DSC exhibited a stable antigen phenotype highly similar to that of these cells in vivo. Flow cytometry results confirmed that DSC cultured in fibroblast medium expressed CD34 protein, and reverse transcription-polymerase chain reaction findings showed that they have CD34 mRNA. Decidual stromal cells were also positive for STRO-1, an antigen that identifies stromal precursors of the bone marrow which also expresses CD34. The expression of CD10, CD13, alkaline phosphatase and alpha-smooth muscle actin by DSC, and the absence of expression of CD14 and CD45, further confirmed their relationship with the stromal precursors.