BCR-ABL1 tyrosine kinase and Src-family tyrosine kinases (BCR-ABL1 (for the fusion oncoprotein), Src-family tyrosine kinases (SFKs))

BCR-ABL1 tyrosine kinase is an oncogenic fusion protein arising from the Philadelphia chromosome (t[9;22] translocation), characterized by constitutive, deregulated kinase activity that drives chronic myeloid leukemia (CML) and some acute lymphoblastic leukemias. The ABL1 kinase domain shares structural and regulatory similarity with Src-family tyrosine kinases, which are non-receptor cytoplasmic enzymes involved in cell signaling, growth, and survival. BCR-ABL1 activates multiple downstream pathways (such as JAK/STAT, RAS/MAPK, PI3K/AKT) resulting in increased proliferation, reduced apoptosis, and cytoskeletal alterations. Src-family kinases, a group of nine homologous enzymes (Src, Fyn, Yes, Lyn, Lck, Hck, Blk, Fgr, and Yrk), are important in diverse cellular processes including immune signaling and tumor progression. Both BCR-ABL1 and Src-family tyrosine kinases are validated therapeutic targets in oncology, with multiple small-molecule tyrosine kinase inhibitors approved or in clinical development targeting these enzymes. Resistance mutations, particularly in the ATP binding domain, are a major therapeutic challenge for both target classes[2][3][4][5][7].

Other names

BCR-ABL (for the fusion protein, various isoforms: p210, p190, p230)Abelson murine leukemia viral oncogene homolog 1 (ABL1)Src-family tyrosine kinases (SFKs) include: c-Src, Fyn, Yes, Lyn, Lck, Hck, Blk, Fgr, Yrk

ATP-competitive inhibition of kinase domain to block phosphorylation and downstream signaling Allosteric inhibition (asciminib for BCR-ABL1) Inhibition of autophosphorylation and substrate phosphorylation