Abstract 5591: Development of a BCR-ABL degrader overcoming resistance by BCR-ABL1 kinase domain mutations in chronic myeloid leukemia

Abstract Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML, yielding remarkable responses in patients. However, resistance mutations within the BCR-ABL1 kinase domain can arise, leading to treatment failure and disease progression. In this study, we report the identification of potent, orally efficacious BCR-ABL1 PROTACs. UBX-362 exhibits strong degradation activity against BCR-ABL1 proteins in CML cell lines. Consistently, it effectively suppresses cell viability in these cell lines, with low nanomolar IC50 values. Additionally, we evaluated the effects of single and combination therapies with TKIs (Asciminib or Ponatinib) using cell proliferation assays in K562 and Ba/F3 BCR-ABL1 mutant cell lines. Co-treatment of UBX-362 with Asciminib or Ponatinib resulted in a synergistic anti-proliferative effect in K562 cells. Notably, the combination of UBX-362 and Asciminib showed synergistic growth-inhibitory effects in Ba/F3 cell lines harboring BCR-ABL1 mutations. Oral administration of UBX-362 significantly reduced BCR-ABL1 protein levels in tumor tissue and robustly inhibited tumor growth in a CML CDX mouse model. These preclinical findings suggest the potential for the clinical development of a BCR-ABL1 degrader. Furthermore, UBX-362 demonstrates the ability to overcome resistance in CML patients with BCR-ABL1 mutations and shows promise as a candidate for combination therapy with other BCR-ABL1 inhibitors, providing new therapeutic possibilities for CML patients. Citation Format: Ye Seul Lim, Na-rae Jeong, Sun-Mi Yoo, Han Wool Kim, So Hyuk Kim, Hyun-Hwi Kim, Yongdae Kwon, Heejung Moon, Hohyun Lee, Jungmin Ahn, Jihye Lee, Je Ho Ryu, Song Hee Lee. Development of a BCR-ABL degrader overcoming resistance by BCR-ABL1 kinase domain mutations in chronic myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5591.