Chronic myeloid leukemia (CML) is a clonal hematopoietic malignancy characterized by the presence of the Philadelphia chromosome, which generates the constitutively active BCR::ABL1 tyrosine kinase, driving uncontrolled myeloid proliferation. Although BCR::ABL1-targeted tyrosine kinase inhibitors (TKIs) have significantly improved CML management, challenges such as drug resistance, intolerance, and long-term adverse effects persist. To overcome these limitations, recent research has focused on developing next-generation TKIs and alternative molecular scaffolds capable of bypassing resistance mechanisms. Among these, five-membered heterocyclic compounds have gained considerable attention due to their structural diversity, favorable pharmacokinetic properties, and ability to interact with multiple biological targets. Several clinically relevant agents, including dasatinib, ponatinib, and asciminib, incorporate such heterocyclic frameworks, highlighting their therapeutic significance. In addition to direct inhibition of BCR::ABL1, these compounds can modulate key signaling pathways involved in CML progression, such as PI3K/Akt, MAPK, and JAK/STAT. This review explores the chemical diversity, molecular interactions, and therapeutic potential of five-membered heterocyclic compounds in CML. Overall, these scaffolds represent promising candidates for developing more effective and less toxic treatment strategies, improving long-term patient outcomes.
Ninave et al. (Tue,) studied this question.