Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation

Satoshi Yamanaka, Hirotake Furihata, Yuta Yanagihara, Akihito Taya, Takato Nagasaka, Mai Usui, Koya Nagaoka, Yuki Shoya, Kohei Nishino, Shuhei Yoshida, Hidetaka Kosako, Masaru Tanokura, Takuya Miyakawa, Yuuki Imai, Norio Shibata and Tatsuya Sawasaki ()
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Satoshi Yamanaka: Ehime University
Hirotake Furihata: Ehime University
Yuta Yanagihara: Ehime University
Akihito Taya: Nagoya Institute of Technology
Takato Nagasaka: Nagoya Institute of Technology
Mai Usui: Nagoya Institute of Technology
Koya Nagaoka: Ehime University
Yuki Shoya: Ehime University
Kohei Nishino: Tokushima University
Shuhei Yoshida: Ehime University
Hidetaka Kosako: Tokushima University
Masaru Tanokura: The University of Tokyo
Takuya Miyakawa: The University of Tokyo
Yuuki Imai: Ehime University
Norio Shibata: Nagoya Institute of Technology
Tatsuya Sawasaki: Ehime University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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 CRL4CRBN. 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.

Date: 2023
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DOI: 10.1038/s41467-023-40385-9

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