2. Academic Validation
  3. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase

A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase

  • Nature. 2016 Jul 14;535(7611):252-7. doi: 10.1038/nature18611.
Mary E Matyskiela 1,  Gang Lu 1,  Takumi Ito 2,  Barbra Pagarigan 1,  Chin-Chun Lu 1,  Karen Miller 1,  Wei Fang 1,  Nai-Yu Wang 1,  Derek Nguyen 1,  Jack Houston 1,  Gilles Carmel 1,  Tam Tran 1,  Mariko Riley 1,  Lyn'Al Nosaka 3,  Gabriel C Lander 3,  Svetlana Gaidarova 1,  Shuichan Xu 1,  Alexander L Ruchelman 1,  Hiroshi Handa 2,  James Carmichael 1,  Thomas O Daniel 1,  Brian E Cathers 1,  Antonia Lopez-Girona 1,  Philip P Chamberlain 1
Affiliations

Affiliations

  • 1 Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
  • 2 Department of Nanoparticle Translational Research, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan.
  • 3 The Scripps Research Institute, San Diego, California 92121, USA.
PMID: 27338790 DOI: 10.1038/nature18611
Abstract

Immunomodulatory drugs bind to Cereblon (CRBN) to confer differentiated substrate specificity on the CRL4(CRBN) E3 ubiquitin Ligase. Here we report the identification of a new Cereblon Modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN-DDB1-CC-885-GSPT1 complex reveal that GSPT1 binds to Cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a 'hotspot' on the Cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known Cereblon substrates, mutational analysis and modelling indicate that the Cereblon substrate Ikaros uses a similar structural feature to bind Cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying Cereblon 'neosubstrate' selectivity, and identify an anti-tumour target rendered druggable by Cereblon modulation.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z