Abelson tyrosine-protein kinase and Src family kinases (ABL/SFK)

Abelson tyrosine-protein kinases (ABL1 and ABL2) and Src-family kinases (SFKs) are critical non-receptor tyrosine kinases that mediate essential cellular processes, including growth, survival, and cytoskeletal organization [UniProt P00519, P12931]. The ABL family is famously linked to the BCR-ABL1 fusion protein, the primary driver of chronic myeloid leukemia (CML), while SFKs like Src, Lyn, and Fyn are frequently upregulated in various cancers where they promote metastasis and drug resistance [PubMed: 17401429]. Because SFKs can phosphorylate and activate ABL or provide alternative survival signals, dual inhibition of both ABL and SFKs is a potent therapeutic strategy to overcome resistance to selective ABL inhibitors like imatinib [PubMed: 15145811]. Drugs such as dasatinib and bosutinib are designed to bind the ATP-binding pocket of these kinases, effectively shutting down downstream signaling in Philadelphia chromosome-positive leukemias [FDA Label: Dasatinib]. Beyond hematologic malignancies, these kinases are also targeted in clinical trials for solid tumors due to their role in regulating cell motility and invasion [PubMed: 24033831]. The therapeutic utility of targeting this group lies in the ability to disrupt multiple nodes of the oncogenic signaling network simultaneously. However, the broad activity of these inhibitors can lead to off-target effects and specific toxicities like pleural effusion or myelosuppression [PubMed: 19071001].

Other names

ABL/SrcAbelson-related kinases and Src-family kinasesNon-receptor tyrosine kinases ABL and SRCBCR-ABL and Src kinases

Dual inhibition of ABL and Src-family kinases via competitive binding to the ATP-binding site within the catalytic domain, which prevents the phosphorylation of tyrosine residues on substrate proteins and interrupts downstream oncogenic signaling pathways [PubMed: 15145811, 17401429].