Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK)
Open accessAbstract
We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1).
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Both PROTACs reduced downstream signalling and proliferation of ALK-driven cell lines by degrading ALK.
“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 [79]
ALK was degraded by two PROTACs based on a pomalidomide warhead targeting CRBN linked with either LDK378 (ceritinib) or TAE684.
“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 [79]
PROTACs and IMiDs are generally larger and more flexible than typical drug-like compounds, which can translate into poor membrane permeability and liability to efflux pumps.
“These molecules are generally larger and more flexible than typical drug-like compounds, which can translate into poor membrane permeability and liability to efflux pumps 39,42,43 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [42]
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- Authors
- Powell, C. E., Gao, Y., Tan, L., Donovan, K. A., Nowak, R. P., Loehr, A., Bahcall, M., Fischer, E. S., Jänne, P. A., George, R. E., & Gray, N. S.
- Affiliations
- Harvard University (US)
- Boston Children's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Gray, Nathanael S.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-04-16
- Volume
- 61
- Issue
- 9
- Pages
- 4249-4255
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC6294449
- OpenAlex
- W2801986983
- Cited by
- 198
- References
- 35
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 20 · 2023: 30 · 2022: 23 · 2021: 28 · 2020: 37 · 2019: 20 · 2018: 4
- FWCI
- 8.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health and Human Services (R01 CA148688, R01 CA136851-08, R01 CA214608-01, 5 T32 GM095450-04, 2 T32 GM007306-40)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- anaplastic lymphoma kinase, small-molecule degraders, protein degradation, TAE684, pomalidomide, non-small cell lung cancer, anaplastic large cell lymphoma, neuroblastoma, focal adhesion kinase, AURKA, FER, RSK1
- MeSH terms
- Anaplastic Lymphoma Kinase, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Pyrimidines, Sulfones, Cell Line, Tumor, Protein Kinase Inhibitors, Proteolysis
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