Overcoming drug resistance remains a major challenge in targeted therapy. Molecular glue degraders offer a promising solution, but their discovery has been largely serendipitous, limiting systematic development. In this study, we report a rational strategy to convert kinase inhibitors into molecular glue degraders that overcome Bcr-AblT315I-mediated resistance in chronic myeloid leukemia (CML). By engineering the solvent-exposed region of GZD824, we generated a covalent degrader that recruits the previously unexploited E3 ligase UBR4 through covalent engagement of C4512. Structural optimization, which replaced the covalent warhead with a minimal ethyl group, yielded compound 4147. This compound achieved potent Bcr-AblT315I degradation (DC₅₀ = 16.18 nM, Dmax = 91.1%), displayed favorable pharmacokinetics (t1/2 = 4.36 h, F = 69.78%), and demonstrated strong in vivo efficacy (67.8% TGI at 20 mg/kg) with minimal toxicity (≤3% body weight loss), markedly outperforming olverembatinib (26.2% TGI). These findings establish 4147 as a clinically tractable molecular glue degrader to overcome T315I-mediated resistance in CML. More broadly, our design strategy can be applied to other marketed kinase inhibitors, such as imatinib (Gleevec) and ponatinib (Iclusig), through minimal structural modifications that preserve drug-like properties. Beyond its therapeutic implications, this work validates UBR4 as a previously unexploited E3 ligase for targeted protein degradation, thereby expanding the ligase repertoire and providing a general framework for the rational development of druggable molecular glue degraders.