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5012 A Novel BCR-ABL1 Degrader, Ubx-362, Can Overcome Resistance By BCR-ABL1 Kinase Domain Mutations in Chronic Myeloid Leukemia

Program: Oral and Poster Abstracts
Session: 802. Chemical Biology and Experimental Therapeutics: Poster III
Hematology Disease Topics & Pathways:
CML, Chronic Myeloid Malignancies, drug development, Diseases, Therapies, Myeloid Malignancies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Ye Seul Lim1*, Na-Rae Jeong1*, Sun-Mi Yoo2*, Han Wool KIM1*, Song Hee Lee, PhD1* and Dong-Wook Kim, MD, PhD3

1Ubix therapeutics, Seoul, Korea, Republic of (South)
2Ubix therapeutics, Seoul, South Korea
3Uijeongbu Eulji Medical Center, Uijeoungbu-si, Korea, Republic of (South)


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 CML treatment, providing remarkable responses in patients. However, resistance mutations within the BCR-ABL1 kinase domain can emerge, leading to treatment failure and disease progression.


To overcome TKI resistance, we developed a novel BCR-ABL1 degrader (UBX-362), which is a proteolysis-targeting chimera (PROTAC), and investigated its therapeutic potential using several Ba/F3 cell lines expressing various BCR-ABL1 mutations. UBX-362 is designed to target BCR-ABL1 through the ubiquitin-proteasome system-mediated degradation. Proliferation assays (IC50) were performed using the Cell Titer-Glo assay, and western blotting was conducted to measure the degradation levels of the BCR-ABL1 protein in the tested cell lines. For the in vivo xenograft mice experiments, 5 × 106 K562 cells were subcutaneously injected into Balb/c nude mice. UBX-362 will be orally administered at doses of 5 or 20 mg/kg, and dasatinib or ponatinib will be administered at a dose of 20 mg/kg once daily for 21 days.


We identified potent and orally available PROTACs, among which UBX-362 exhibited superior degradation activity against both wild-type (WT) and mutant BCR-ABL1 proteins in various Ba/F3 BCR-ABL1 kinase domain mutant-expressing cell lines. In vitro experiments showed that UBX-362 effectively degrades WT and various mutant BCR-ABL1 proteins. The levels of WT BCR-ABL1 protein were measured by western blotting, yielding a half-maximal degradation concentration of UBX-362 at ~1.78 nM. Furthermore, the DC50 of UBX-362 against E255K, V299L, F317L, and F359C mutant BCR-ABL1 proteins were in the single-digit nM range (6.395nM, 7.679nM, 4.635nM, and 5.688nM, respectively). While UBX-362's anti-proliferative activity (~2.562nM) was not found to be superior to dasatinib (~0.378nM), it still demonstrated a strong anti-proliferative effect in the CML cell line K562 and various BCR-ABL1 mutant-expressing Ba/F3 cell lines. Specifically, the IC50 of UBX-362 was 2.477nM in the Ba/F3 WT cell line. An in vivo anti-cancer efficacy study is currently underway in the K562 xenograft mouse model to compare its effectiveness with dasatinib or ponatinib.


The findings from this pre-clinical study show the possibility of clinical development of a BCR-ABL1 degrader. And, UBX-362 can overcome resistance in CML patients with BCR-ABL1 mutations and can be a good candidate for further clinical development.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH