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Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK)
Open accessAbstract
Anaplastic lymphoma kinase (ALK) activation has been associated with many types of human cancer. Significant efforts have been devoted to the development of ALK inhibitors to antagonize the kinase activity of ALK. Four ALK inhibitors have been approved by the FDA to date for treating patients with ALK-positive non-small cell lung cancers (NSCLC). However, drug resistance has been observed in the majority of patients treated with these inhibitors. New therapeutic strategies (e.g., compounds with novel mechanisms of action) are needed to overcome the drug resistance issue. The emerging PROTAC (Proteolysis Targeting Chimera) technology has been successfully applied to selective degradation of multiple protein targets, but not ALK. Since ALK protein levels are not important for viability in mammals, ALK PROTACs could lead to novel therapeutics with minimal toxicity. Here we report the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. MS4077 (5) and MS4078 (6) potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds 5 and 6 was cereblon and proteasome dependent. In addition, compounds 5 and 6 potently inhibited proliferation of SU-DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. We also developed MS4748 (7) and MS4740 (8), very close analogs of 5 and 6 respectively, which are incapable to degrade the ALK fusion proteins, as negative controls. Compounds 5-8 are valuable chemical tools for investigating effects of ALK pharmacological degradation. Our study paved the way for developing the next generation of ALK PROTACs.
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“Recently, PROTACs were shown to be substrates for MDR1 (10, 13), suggesting that drug efflux represents a potential limitation for degrader therapies.”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [13]
In the citing paper
“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 [5]
In the citing paper
“Recently, the anaplastic lymphoma kinase (ALK) was degraded by two PROTACs based on a pomalidomide warhead targeting CRBN linked with either LDK378 (ceritinib) [79, 80] or TAE684 [79] targeting ALK.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [80]
In the citing paper
“Both PROTACs were able to reduce downstream signalling and proliferation of ALK-driven cell lines by degrading ALK [79, 80].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [80]
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Citations
Cites
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First-Line Crizotinib versus Chemotherapy in ALK -Positive Lung Cancer
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Fusion of a Kinase Gene, ALK , to a Nucleolar Protein Gene, NPM , in Non-Hodgkin's Lymphoma
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An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
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Ceritinib in ALK -Rearranged Non–Small-Cell Lung Cancer
Shaw, A. T., Kim, D.-W., Mehra, R., Tan, D. S. W., Felip, E., Chow, L. Q. M., Camidge, D. R., Vansteenkiste, J., Sharma, S., De Pas, T., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1311107 · Cited by 1,495
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486
Proteasome inhibitors: valuable new tools for cell biologists.
Lee, D. H., & Goldberg, A. L. (1998) · Trends in Cell Biology · doi:10.1016/s0962-8924(98)01346-4 · Cited by 1,474
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PROteolysis TArgeting Chimeras (PROTACs) — Past, present and future
Pettersson, M., & Crews, C. M. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.01.002 · Cited by 830
Trends in kinase drug discovery: targets, indications and inhibitor design
Attwood, M. M., Fabbro, D., Sokolov, A. V., Knapp, S., & Schiöth, H. B. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00252-y · Cited by 850
Advancing targeted protein degradation for cancer therapy
Dale, B., Cheng, M., Park, K., Kanıskan, H. Ü., Xiong, Y., & Jin, J. J. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00365-x · Cited by 697
Self-citationPROTACs: great opportunities for academia and industry
Sun, X., Gao, H., Yang, Y., He, M., Wu, Y., Song, Y.-G., Tong, Y., & Rao, Y. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0101-6 · Cited by 663
Metadata
- Authors
- Zhang, C., Han, X.-R., Yang, X., Jiang, B., Liu, J., Xiong, Y., & Jin, J.
- Affiliations
- Tisch Cancer Institute (US)
- ShanghaiTech University (CN)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Liu, Jing
- Xiong, Yue
- Jin, Jian
- Venue
- European Journal of Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 151
- Pages
- 304-314
- ISSN
- 0223-5234 (ISSN-L)
- PMC
- PMC5924614
- OpenAlex
- W2794623623
- Cited by
- 226
- References
- 57
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 24 · 2023: 26 · 2022: 31 · 2021: 31 · 2020: 38 · 2019: 26 · 2018: 9
- FWCI
- 9.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U. S. National Institutes of Health (R01GM067113)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- PROTACs, anaplastic lymphoma kinase, cereblon ligands, proteasomal degradation, ALK fusion proteins, drug resistance, non-small cell lung cancer, ALK-positive lymphoma, pharmacokinetics, kinase inhibitors
- MeSH terms
- Anaplastic Lymphoma Kinase, Animals, Antineoplastic Agents, Humans, Lung Neoplasms, Lymphoma, Male, Drug Design, Signal Transduction, Receptor Protein-Tyrosine Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Mice, Proteolysis
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