And Doriano Fabbro PhD

ABL, C-KIT, AND PLATELET-DERIVED GROWTH FACTOR RECEPTOR INDICATIONS FOR IMATINIB OTHER THAN CANCER EPIDERMAL GROWTH FACTOR RECEPTOR SMALL-MOLECULE INHIBITORS OF EGFR AND HER2 VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR NONCANCER VEGF-TARGETED THERAPIES NOVEL TYROSINE KINASE TARGETS CLINICAL QUESTIONS CONCLUSIONS AND PERSPECTIVES The identification and characterization of the members of individual signal transduction cascades, and advances in understanding how these signals are integrated in...

JAKs in Multiple Myeloma

Recent studies indicate that the activation of the JAK STAT pathway plays an important role in the pathophysiology of MM. In malignant plasma cells, STAT3 is strongly activated by IL-6, a major growth and survival factor, which is mainly produced in the myeloma bone marrow microenvironment (108,109). This has been shown for a number of cell lines, but even more important, STAT3 was found to be constitutively activated in tumor samples from patients with MM (110,111). Interestingly, constitutive...

PDGF and Fibrotic Disease

The biological activities of PDGF, i.e., stimulation of fibroblast proliferation and matrix production, are compatible with a causal role of PDGF in development of different fibrotic conditions. Among the fibrotic conditions, glomerol-unephritis and lung fibrosis have been studied in most detail with regard to possible involvement of PDGF receptor signaling. A therapeutic potential for PDGF antagonists in treatment of renal disease has been suggested by findings that PDGF and its receptors are...

Outlook Src As A Target For Other Indications More Selective And Dual Src Inhibitors

The application of Src inhibitors for inhibition of benign bone loss in postmenopausal osteoporosis remains questionable. High safety requirements for this indication and unacceptable side effects of the compounds examined seem to preclude further development of current compounds. Apart from a few isolated studies, the potential of Src inhibitors for inhibition of different tumors has not yet been extensively examined. A lack of enthusiasm in this area is certainly caused by a lack of...

Src Inhibitors Activity In Vitro

We will now describe the in vitro activity of pyrrolopyrimidines and olomoucines, for which we have the most extensive information available. In vitro and in vivo effects of the pyrrolopyrimidine CGP77675 on Src activity and bone resorption have been previously reported (18). Briefly, CGP77675 inhibits human Src in enzymatic assays and cellular Src in an Src-overexpress-ing cell line with IC50 values of 20 and 200 nM, respectively. This compound was active in assays of in vitro osteoclast bone...

Application

Given the in vivo activity of Src inhibitors in models of bone resorption, what are the chances for the development of therapeutic agents from these compounds A main indication for the pharmacological inhibition of bone loss is Fig. 6. Src inhibitor of the pyrrolopyrimidine class reduces prostrate cancer cell migration and invasion. PC3 prostate cancer cells were cultured in Boyden's chambers on porous membranes coated with gelatin or Matrigel and either left untreated (black bars) or treated...

Pharmacological Inhibition Of Jaks

Autoimmune Jak

Few selective JAK inhibitors are currently available, which are mostly used in cell culture studies to confirm the connection of the JAK-STAT pathway to certain biological functions such as cell growth, survival, differentiation, or drug resistance (features of selected JAK inhibitors are summarized in Table 3). Some studies have been performed in animal models. To our knowledge, there are no JAK inhibitors in clinical trials yet. The probably best known and characterized JAK inhibitor is AG490...

Structures Of Ptks

Map Kinase

PTKs have been studied extensively using structural biology over the past 15 yr, with the first atomic structure of a tyrosine kinase domain appearing in 1994 (1). As of November 2003, there were 21 entries for nonreceptor PTKs and 24 entries for receptor PTKs in the protein data bank (PDB). In some cases, because of the high value of structures for drug design, structures have been published (some only in patents), but the coordinates are not yet publicly available. The tyrosine kinase domain...

PDGF in Malignant Disease

Initial evidence for the involvement of PDGF in tumorigenesis came with the discovery of homology between the PDGF-B gene and the simian sarcoma viral oncogene v-sis 84,85 . The transforming activity of the sis gene product occurs by autocrine stimulation of PDGF receptors reviewed in ref. 86 . Autocrine stimulation by PDGF-A, -C, and -D also transforms PDGF receptor-expressing cells 87,88 . In addition, there are mutational events that cause constitutive activation of PDGF receptors Fig. 3 ....