Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide

Hirotake Furihata,Takuya Miyakawa,Yumiko Miyauchi,Atsuko Asano,Satoshi Yamanaka,Norio Shibata,Toshiaki Honda,Masaru Tanokura,Tatsuya Sawasaki

doi:10.1038/s41467-020-18488-4

Hirotake Furihata, Takuya Miyakawa + Show 7 more

Open Access

https://doi.org/10.1038/s41467-020-18488-4

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Abstract

Thalidomide and its derivatives exert not only therapeutic effects as immunomodulatory drugs (IMiDs) but also adverse effects such as teratogenicity, which are due in part to different C2H2 zinc-finger (ZF) transcription factors, IKZF1 (or IKZF3) and SALL4, respectively. Here, we report the structural bases for the SALL4-specific proteasomal degradation induced by 5-hydroxythalidomide, a primary thalidomide metabolite generated by the enzymatic activity of cytochrome P450 isozymes, through the interaction with cereblon (CRBN). The crystal structure of the metabolite-mediated human SALL4-CRBN complex and mutagenesis studies elucidate the complex formation enhanced by the interaction between CRBN and an additional hydroxy group of (S)-5-hydroxythalidomide and the variation in the second residue of β-hairpin structure that underlies the C2H2 ZF-type neo-morphic substrate (neosubstrate) selectivity of 5-hydroxythalidomide. These findings deepen our understanding of the pharmaceutical action of IMiDs and provide structural evidence that the glue-type E3 ligase modulators cause altered neosubstrate specificities through their metabolism.

Highlights

Thalidomide and its derivatives exert therapeutic effects as immunomodulatory drugs (IMiDs) and adverse effects such as teratogenicity, which are due in part to different C2H2 zinc-finger (ZF) transcription factors, IKZF1 and spaltlike transcription factor 4 (SALL4), respectively
Since it has been demonstrated that thalidomide and its derivatives, lenalidomide and pomalidomide, have immunomodulatory activity and anti-proliferative effects on several hematological cancers, they are widely applied for the therapy of multiple myeloma and other hematologic malignancies as immunomodulatory drugs (IMiDs) despite their adverse effects[4,5,6,7]
The results suggest that the 5-hydroxylation of the phthalimide moiety does not affect the enantioselectivity of thalidomide for the SALL4–CRBN complex

Summary

Introduction

Thalidomide and its derivatives exert therapeutic effects as immunomodulatory drugs (IMiDs) and adverse effects such as teratogenicity, which are due in part to different C2H2 zinc-finger (ZF) transcription factors, IKZF1 (or IKZF3) and SALL4, respectively. The crystal structure of the metabolite-mediated human SALL4-CRBN complex and mutagenesis studies elucidate the complex formation enhanced by the interaction between CRBN and an additional hydroxy group of (S)-5-hydroxythalidomide and the variation in the second residue of β-hairpin structure that underlies the C2H2 ZF-type neo-morphic substrate (neosubstrate) selectivity of 5-hydroxythalidomide. These findings deepen our understanding of the pharmaceutical action of IMiDs and provide structural evidence that the glue-type E3 ligase modulators cause altered neosubstrate specificities through their metabolism. The crystal structure of the 5HT-mediated human SALL4–CRBN complex and mutagenesis studies elucidate that the complex formation is enhanced by the interaction between

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