Oncopharmacological aspects of Bcr-Abl inhibitors: from revolutionary structure-based design to clinical resistance

Chronic myeloid leukaemia (CML) represents the first oncological disease in which a direct relationship between a genetic mutation and neoplasia formation has been established. The Philadelphia chromosome leads to the expression of a tyrosine kinase with constitutive activity, providing the basis for the development of targeted pharmacotherapy. The introduction of imatinib marked the beginning of the era of tyrosine kinase inhibitors (TKIs) and significantly improved prognosis and long-term survival in CML. Despite these advances, a subset of patients requires treatment modification due to resistance, intolerance, or loss of response, while the need for continuous or lifelong therapy increases the risk of cumulative adverse effects. Together, kinase domain mutations, compound mutations, Bcr-Abl–independent resistance mechanisms, and off-target toxicity expose the practical limits of ATP-competitive inhibition. This review critically examines the evolution of Bcr-Abl inhibitors in light of these constraints and evaluates alternative strategies to achieve more durable disease control.