Bcr Abl and Src Kinase Inhibitors - Biotech, Pharma and Life Science Channel
Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome, which results from a reciprocal translocation between the long arms of the chromosomes 9 and 22 t(9;22)(q34;q11). This translocation creates two new genes, BCR-ABL on the 22q- (Ph chromosome) and the reciprocal ABL-BCR on 9q-. The “breakpoint cluster region/Abelson” (BCR-ABL) gene encodes for a 210-kD protein with deregulated tyrosine kinase (TK) activity, which is crucial for malignant transformation in CML. The recognition of the BCR-ABL gene and corresponding protein led to the synthesis of small-molecule drugs, designed to interfere with BCR-ABL tyrosine kinase activation by competitive binding at the ATP-binding site. The first tyrosine kinase inhibitor (TKI), introduced into clinical practice in 1998, was imatinib mesylate.
The advent of imatinib, a selective inhibitor of the ABL tyrosine kinase, has revolutionized the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Combined with chemotherapy, imatinib exerts remarkable efficacy in patients with newly diagnosed disease. Despite such improvement, however, relapse does occur, mainly owing to acquisition of resistance.
Growing comprehension of the molecular mechanisms of resistance to imatinib has led to the development of novel BCR-ABL inhibitors that yield higher affinity for BCR-ABL and/or potent inhibitory activity against other target molecules such as SRC family kinases. The second-generation ABL kinase inhibitors, namely dasatinib and nilotinib, are already showing clinical activity in patients with imatinib-resistant Ph+ ALL, and other novel agents are undergoing preclinical and early clinical evaluation.
The c-Src protein is a 60-kDa nonreceptor tyrosine kinase that is emerging as a potential target for cancer therapy. c-Src regulates signals from multiple cell surface molecules, including integrins, growth factors , and G protein–coupled receptors. Elevated c-Src protein levels and/or kinase activity has been reported in a variety of cancers, including HNSCC. The activation of c-Src has been reported to mediate several aspects of tumor growth and progression, including proliferation, migration, invasion, survival, and angiogenesis.
Source; MindBranch (Competitor Analysis: Bcr-Abl and Src Kinase Inhibitors)
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Medical and Biotech [MESH] Definitions
Taxodium
A plant genus of the family TAXODIACEAE. Members contain taxodione and taxodone, which are diterpenoid quinone methide tumor inhibitors.
Huperzia
A plant genus of the family LYCOPODIACEAE. Members contain huperzine, one of the CHOLINESTERASE INHIBITORS.
Receptor, Ephb6
An eph family receptor found primarily in BRAIN and THYMUS. The EphB6 receptor is unusual in that its tyrosine kinase domain shares little homology with other members of this class. The unusual tyrosine kinase domain of this receptor appears to result in its lack of tyrosine kinase activity.
Glycogen Synthase Kinase 3
A glycogen synthase kinase that was originally described as a key enzyme involved in glycogen metabolism. It regulates a diverse array of functions such as CELL DIVISION, microtubule function and APOPTOSIS.
Ribosomal Protein S6 Kinases, 90-kda
A family of ribosomal protein S6 kinases that are structurally distinguished from RIBOSOMAL PROTEIN S6 KINASES, 70-KDA by their apparent molecular size and the fact they contain two functional kinase domains. Although considered RIBOSOMAL PROTEIN S6 KINASES, members of this family are activated via the MAP KINASE SIGNALING SYSTEM and have been shown to act on a diverse array of substrates that are involved in cellular regulation such as RIBOSOMAL PROTEIN S6 and CAMP RESPONSE ELEMENT-BINDING PROTEIN.
