Src family tyrosine-protein kinase and Tyrosine-protein kinase ABL1 (SFKs, ABL1)

Src family kinases are a major class of non-receptor tyrosine kinases consisting of nine known members (Src, Yes, Fyn, Fgr, Lck, Hck, Blk, Lyn, Frk) that play central roles in the regulation of cell proliferation, survival, migration, adhesion, and immune response. They share a conserved multi-domain structure (SH2, SH3, kinase domain) and are involved in various intracellular signaling cascades by phosphorylating tyrosine substrates, frequently acting downstream of growth factor receptors and adhesion proteins. Deregulation or overactivation of Src family kinases is implicated in diverse malignancies and inflammatory diseases. ABL kinases (mainly ABL1 and ABL2) are non-receptor tyrosine kinases involved in the regulation of the cytoskeleton, cell survival, differentiation, response to DNA damage, and cell migration. The best-known clinical significance of ABL is its role in the fusion oncogene BCR-ABL1, derived from chromosomal translocation (the Philadelphia chromosome) in chronic myelogenous leukemia. Drugs targeting ABL and Src kinases have revolutionized the therapy of CML and are under investigation for other cancers and inflammatory diseases. Both kinase families are important therapeutic targets because of their fundamental roles in cell signaling and cancer biology; many small-molecule inhibitors have been developed against them, with imatinib (for BCR-ABL1) as the prototype targeted kinase inhibitor drug. Their inhibition can also modulate responses in infectious and autoimmune diseases, but off-target effects and resistance present major clinical challenges.

Other names

SFKProto-oncogene tyrosine-protein kinase Srcc-Srcc-Fync-YesLckLynHckFgrBlkYrkFrkABLc-AblABL1Abelson murine leukemia viral oncogene homolog 1ABL2 (Arg)

Inhibition of kinase activity: Most drugs are ATP-competitive inhibitors, blocking the active site, preventing phosphorylation of downstream targets, and thereby inhibiting downstream aberrant signaling that drives malignancy or inflammation. - Disruption of protein-protein interactions: Some compounds inhibit SH2/SH3 mediated interactions or substrate/adaptor binding. - Prevention of oncogenic fusion activity: Drugs like imatinib prevent BCR-ABL–driven transformation in CML