2. Academic Validation
  3. Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation

Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation

  • Nat Commun. 2023 Aug 18;14(1):4683. doi: 10.1038/s41467-023-40385-9.
Satoshi Yamanaka 1 2,  Hirotake Furihata 1 3,  Yuta Yanagihara 4,  Akihito Taya 5,  Takato Nagasaka 5,  Mai Usui 5,  Koya Nagaoka 1,  Yuki Shoya 1,  Kohei Nishino 6,  Shuhei Yoshida 4,  Hidetaka Kosako 6,  Masaru Tanokura 3,  Takuya Miyakawa 3 7,  Yuuki Imai 4,  Norio Shibata 5,  Tatsuya Sawasaki 8
Affiliations

Affiliations

  • 1 Division of Cell-Free Sciences, Proteo-Science Center, Ehime University, Matsuyama, 790-8577, Japan.
  • 2 Division of Proteo-Interactome, Proteo-Science Center, Ehime University, Matsuyama, 790-8577, Japan.
  • 3 Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, 113-8657, Japan.
  • 4 Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Toon, 791-0295, Japan.
  • 5 Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Nagoya, 466-8555, Japan.
  • 6 Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima, 770-8503, Japan.
  • 7 Graduate School of Biostudies, Kyoto University, Kyoto, 606-8502, Japan.
  • 8 Division of Cell-Free Sciences, Proteo-Science Center, Ehime University, Matsuyama, 790-8577, Japan. sawasaki@ehime-u.ac.jp.
PMID: 37596276 DOI: 10.1038/s41467-023-40385-9
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.

Figures
Products