Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase
Abstract
The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite great progress for CML treatment through application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, long-term drug administration and clinical resistance continue to be an issue. Herein, we described the design, synthesis, and evaluation of novel proteolysis-targeting chimeric (PROTAC) small molecules targeting BCR-ABL which connect dasatinib and VHL E3 ubiquitin ligase ligand by extensive optimization of linkers. Our efforts have yielded SIAIS178 ( 19 ), which induces proper interaction between BCR-ABL and VHL ligase leading to effective degradation of BCR-ABL protein, achieves significant growth inhibition of BCR-ABL + leukemic cells in vitro, and induces substantial tumor regression against K562 xenograft tumors in vivo. In addition, SIAIS178 also degrades several clinically relevant resistance-conferring mutations. Our data indicate that SIAIS178 as efficacious BCR-ABL degrader warrants extensive further investigation for the treatment of BCR-ABL + leukemia.
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A number of PROTACs have been developed to target various proteins of interest involved in the tumorigenesis and progression of hematologic malignancies, including ALK, Bcl-xL, BCR-ABL, BTK, BRD4, CDK-6, FLT-3, HDAC6, and STAT3.
“A number of PROTACs have been developed to target various POIs that are involved in the tumorigenesis and progression of hematologic malignancies, such as anaplastic lymphoma kinase (ALK) [5], Bcl-xL [4], BCR-ABL [6], Bruton’s tyrosine kinase (BTK) [7], BRD4 [8], CDK-6 [9], FMS-like tyrosine kinase-3 (FLT-3) [10], HDAC6 [11], and signal transducer and activator of transcription 3 (STAT3) [3].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [6]
SIAIS178 was able to degrade several mutant forms of BCR-ABL.
“More importantly, SIAIS178 was able to degrade several mutant forms of BCR-ABL [6].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [6]
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- Authors
- Zhao, Q., Ren, C., Liu, L., Chen, J., Shao, Y., Sun, N., Sun, R., Kong, Y., Ding, X., Zhang, X., Xu, Y., Yang, B., Yin, Q., Yang, X., & Jiang, B.
- Affiliations
- Chinese Academy of Sciences (CN)
- ShanghaiTech University (CN)
- Anhui Medical University (CN)
- Corresponding author
- Yin, Qianqian
- Yang, Xiaobao
- Jiang, Biao
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-09-20
- Volume
- 62
- Issue
- 20
- Pages
- 9281-9298
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2973306386
- Cited by
- 134
- References
- 50
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 23 · 2023: 20 · 2022: 25 · 2021: 14 · 2020: 22 · 2019: 2
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Science Foundation of Shanghai (19ZR1433600)
- China Postdoctoral Science Foundation (2018M642110, 2018M642112, 2019M651609, 2018M632181)
- Science and Technology Commission of Shanghai Municipality (17YF1412200)
- National Natural Science Foundation of China (81702600)
- Jing Medicine Technology Ltd.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- BCR-ABL, PROTACs, protein degradation, chronic myeloid leukemia, dasatinib, linker optimization, tyrosine kinase inhibitor resistance, small-molecule degraders
- MeSH terms
- Animals, Cell Survival, Drug Evaluation, Preclinical, Humans, Piperazines, Structure-Activity Relationship, Transplantation, Heterologous, Drug Design, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Fusion Proteins, bcr-abl, Mice, SCID, Mice, Inbred NOD, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Small Molecule Libraries
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