Kinase c-Abl

Hallaert DY, Jaspers A, van Noesel CJ et al (2008) c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL implications for therapeutic targeting of chemoresis-tant niches. Blood 112 5141-5149... 

Fig. 7 Structure of imatinib (space-filling model) complex with c-Abl kinase (cartoon) from PDB (2HYY) after 500 ps of dynamics simulation in periodic box of TIP3P water. Figure prepared using Pymol...

Dubey KD, Ojha RP (2012) Conformational flexibility, binding energy, role of salt bridge and alanine-mutagenesis for c-Abl kinase complex. J Mol Model 18(5)4679-1689... 

Activation of c-Abl kinase activity and transformation by a chemical inducer of dimerization, J. Biol. Chem. 2001, 276, 24372-24379. 

EPL, a FRET pair, tetramethylrhodamine and fluorescein, was incorporated in c-Crk-II. By judicious placement of the fluorophores within the c-Crk-II molecule, it was possible to monitor the phosphorylation state of the protein using FRET measurements (Fig. 10.1-6). In a subsequent study, an extremely sensitive dual labeled c-Crk-II analog was developed that enabled real-time monitoring of c-Abl kinase activity, and provided a nonradioactive assay for the screening of potential inhibitors of the kinase [69). 

In chronic myelogenous leukemia (CML) as well as in a subset of acute lymphoblastic leukemia (ALL) Bcr-Abl, a fusion protein of c-Abl and the breakpoint cluster region (bcr), is expressed in the cytosol of leukemic cells. This fusion protein forms homo-oligomeric complexes that display elevated kinase activity and is the causative molecular abnormality in CML and certain ALL. The transforming effect of Bcr-Abl is mediated by numerous downstream signaling pathways, including protein kinase C (PKC), Ras-Raf-ERK MAPK, JAK-STAT (see below), and PI3-kinase pathways. 

Several other inhibitors of nonreceptor PTKs are currently in development but only a few of them are studied in clinical trials. Noteworthy, Dasatinib does not only inhibit c-Abl, but also potently blocks Src activity, a property that may contribute to its beneficial clinical effects in CML. Other kinase inhibitors being developed that inhibit c-Abl and/or Src are AZD-0530, AP-23994, PD-0183805, SU-6656, and Bosutinib (SKI-606). Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that decrease bone resorption and may be promising drugs to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

Kipreos, E. T., and Wang, J. Y. J. (1990). Differential phosphorylation of c-abl in cell cycle determined by cdc2 kinase and phophatase activity. Science 248 217-220. 

Crystallography studies showed that imatinib binds to an inactive form of Abl [36,37]. In this bound conformation the activation loop of the Abl kinase domain is distinct from that of both the inactive and active forms of the SFKs, explaining why imatinib does not inhibit these kinases. The crystal structure also revealed that the Thr 315 residue was involved in a key hydrogen bonding interaction with the C-2 amino group of imatinib. 

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