Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation

Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation

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 . Proteolysi...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications Vol. 14; no. 1; p. 4683
Main Authors: Yamanaka, Satoshi, Furihata, Hirotake, Yanagihara, Yuta, Taya, Akihito, Nagasaka, Takato, Usui, Mai, Nagaoka, Koya, Shoya, Yuki, Nishino, Kohei, Yoshida, Shuhei, Kosako, Hidetaka, Tanokura, Masaru, Miyakawa, Takuya, Imai, Yuuki, Shibata, Norio, Sawasaki, Tatsuya
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 18-08-2023
Nature Publishing Group
Nature Portfolio
Subjects:
13/1
13/109
38/77
631/154/309/2419
631/154/556
631/45/474
631/92/2783
82/58
82/83
Antiproliferatives
Biodegradation
Cancer
Chimeras
Degradation
Embryogenesis
Embryonic growth stage
Fetuses
Hematology
Humanities and Social Sciences
Immunomodulation
Immunotherapy
multidisciplinary
Multiple myeloma
Myelodysplastic syndrome
Myelodysplastic syndromes
Proteins
Proteolysis
Science
Science (multidisciplinary)
Selectivity
Targeted cancer therapy
Teratogenicity
Thalidomide
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Lenalidomide is effective for treating several hematological cancers but has teratogenic effect on the fetus. Here, the authors identify modifications that make lenalidomide more selective and effective when used as a stand-alone molecular glue or integrated in PROTACs.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-40385-9