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Cited by 73Protein Degradation and InhibitorsMultiple Myeloma Research and TreatmentsUbiquitin and proteasome pathways

Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation

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Yamanaka, Satoshi, Furihata, Hirotake, Yanagihara, Yuta, Taya, Akihito, Nagasaka, Takato, Usui, Mai, Nagaoka, Koya, Shoya, Yuki +8 more·2023·Nature Communications
DOI 10.1038/s41467-023-40385-9PMC PMC10439208

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Abstract

Lenalidomide, an immunomodulatory drug (IMiD), is commonly used as a first-line therapy in many haematological cancers, such as multiple myeloma (MM) and 5q myelodysplastic syndromes (5q MDS), and it functions as a molecular glue for the protein degradation of neosubstrates by CRL4 CRBN . Proteolysis-targeting chimeras (PROTACs) using IMiDs with a target protein binder also induce the degradation of target proteins. The targeted protein degradation (TPD) of neosubstrates is crucial for IMiD therapy. However, current IMiDs and IMiD-based PROTACs also break down neosubstrates involved in embryonic development and disease progression. Here, we show that 6-position modifications of lenalidomide are essential for controlling neosubstrate selectivity; 6-fluoro lenalidomide induced the selective degradation of IKZF1, IKZF3, and CK1α, which are involved in anti-haematological cancer activity, and showed stronger anti-proliferative effects on MM and 5q MDS cell lines than lenalidomide. PROTACs using these lenalidomide derivatives for BET proteins induce the selective degradation of BET proteins with the same neosubstrate selectivity. PROTACs also exert anti-proliferative effects in all examined cell lines. Thus, 6-position-modified lenalidomide is a key molecule for selective TPD using thalidomide derivatives and PROTACs.

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  • Several non-targeted drugs have been approved for MM treatment, including alkylating agents, corticosteroids, immunomodulatory imide drugs, proteasome inhibitors, histone deacetylase inhibitors, and XPO1 inhibitor.

    “Over the past few decades, several non-targeted drugs have been approved for the treatment of multiple myeloma, including alkylating agents [40], corticosteroids [41–43], immunomodulatory imide drugs (IMiDs) [44–47], proteasome inhibitors (PIs) [42, 48–51], histone deacetylases (iHDACs) inhibitors [37, 52, 53], and XPO1 inhibitor [54–56] (Table 1).”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [47]

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References 72 · Cited by 73

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Authors
Yamanaka, S., Furihata, H., Yanagihara, Y., Taya, A., Nagasaka, T., Usui, M., Nagaoka, K., Shoya, Y., Nishino, K., Yoshida, S., Kosako, H., Tanokura, M., Miyakawa, T., Imai, Y., Shibata, N., & Sawasaki, T.
Affiliations
  • Ehime University (JP)
  • Nagoya Institute of Technology (JP)
  • Fujii Memorial Institute of Medical Sciences, Tokushima University (JP)
  • The University of Tokyo (JP)
  • Kyoto University (JP)
Corresponding author
Sawasaki, Tatsuya
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-08-18
Volume
14
Issue
1
Pages
4683-4683
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-40385-9
PMC
PMC10439208
OpenAlex
W4385980910
Cited by
73
References
72
Citations by year
2026: 22 · 2025: 33 · 2024: 17 · 2023: 1
FWCI
6.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (acceptedVersion, cc-by)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
Funders
  • Japan Agency for Medical Research and Development (22ama121010j0001, JP22cm0106181h0002, JP21cm0106181h0006)
  • MEXT | Japan Society for the Promotion of Science (JP16H06579, JP19H03218, 21H00285, 21K15076, JP17H06112, JP19H04966)
  • Takeda Science Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
PROTACs, immunomodulators, targeted protein degradation, BET proteins, IKZF1, IKZF3, CK1α, multiple myeloma, thalidomide derivatives, antiproliferative activity
MeSH terms
Lenalidomide, Immunomodulating Agents, Proteolysis Targeting Chimera, Chromosome Aberrations, Female, Humans, Multiple Myeloma, Myelodysplastic Syndromes, Pregnancy, Hematologic Neoplasms, Proteolysis

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