Last findings on dual inhibitors of abl and SRC tyrosine-kinases.
Chronic myelogenous leukemia (CML) is a myeloproliferative disease characterized by the presence of the Philadelphia chromosome that expresses the constitutively activated tyrosine kinase Bcr-Abl; this enzyme causes hyperproliferation of the stem cells and the consequent pathology of the disease. Targeted inhibitors of Bcr-Abl have antiproliferative effects on the leukemic cells and induce apoptosis, favouring a regression of the CML chronic phase, but in the successive blast crisis phase cancer cells frequently develop resistance to Bcr-Abl inhibitors. Src is a family of non-receptor tyrosine kinases, fundamental for cell development, growth, replication, adhesion, motility and is overexpressed in a wide number of human cancers. Recently it was demonstrated that Src is increased in hematopoietic cells expressing Bcr-Abl and is involved in the oncogenic pathway that causes CML. For this reason and also for the development of resistance to classical Bcr-Abl inhibitors, various dual Src/Abl inhibitors have been recently synthesized and tested. This mini review will be focused on the latest finding on this matter.
Schenone
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S
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV, I-16132 Genoa, Italy. schensil@unige.it
Manetti
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F
Botta
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D000818:Animals; D006801:Humans; D016374:Oncogene Proteins v-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011687:Purines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D016374:Oncogene Proteins v-abl; D047428:Protein Kinase Inhibitors; D011687:Purines; D011743:Pyrimidines; D019061:src-Family Kinases