Abstract

Inducing protein degradation by proteolysis-targeting chimeras (PROTACs) has gained tremendous momentum in the field for its promise in the discovery and development of new therapies. Based on our previously reported PROTAC BCR-ABL degraders, we designed and synthesized additional 4 PROTAC compounds with a novel linker that contains pyrimidine rings. Molecular and cellular studies have shown that different linkers affect the degradation activity of small-molecule degraders on the target protein of BCR-ABL. We screened out a lead compound, , with stable physicochemical properties and high activity. Preliminary evaluation of its pharmacodynamics in vitro model showed that it has a good inhibitory effect on imatinib-resistant chronic myeloid leukemia cell lines, as has been shown in animal models. Our preliminary research into the mechanism of found that can overcome drug resistance by simultaneously inhibiting the targets of BCR-ABL and SRC-family kinase (SFK).

MeSH

Cells, Src-Family Kinases, Pharmaceutical Preparations, Genes, Abl, Drug Resistance, Small Molecules

Cited by

• PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas. Int J Mol Sci, 2023
• FDA-approved kinase inhibitors in PROTAC design, development and synthesis. J Enzyme Inhib Med Chem, 2025