Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4CRBN 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.

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Protein Data Bank

Data deposits

Coordinates for the structure of cereblon–DDB1–CC-885–GSPT1 have been deposited in the Protein Data Bank with the accession code 5HXB.


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Thanks to G. Reyes, C. Havens, P. Jackson and H. Hadjivassiliou for discussions relating to this manuscript, and P. Jackson, J. Hansen, M. Correa, B. Fahr, M. Abbasian, E. Ambing, E. Rychak, D. Mendy and K. Hughes for technical assistance. We thank K. Motamedchaboki (Proteomics Core, Sanford Burnham Prebys Medical Discovery Institute) for mass spectrometry-based proteomic analysis. Thanks to J. Ballesteros and P. Hernandez at Vivia for patient sample testing. Parts of this work were conducted at the Advanced Light Source. The Berkeley Center for Structural Biology is supported in part by the National Institutes of Health, National Institute of General Medical Sciences, and the Howard Hughes Medical Institute. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under contract No. DE-AC02-05CH11231. This work was also supported by Grant-in-Aid for Scientific Research on Innovative Areas “Chemical Biology of Natural Products” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (23102002 to H.H.), by JST, PRESTO (T.I.) and by Grant-in-Aid for Young Scientists (B) from MEXT (26750374 to T.I.).

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Author notes

    • Mary E. Matyskiela
    • , Gang Lu
    •  & Takumi Ito

    These authors contributed equally to this work.


  1. Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA

    • Mary E. Matyskiela
    • , Gang Lu
    • , Barbra Pagarigan
    • , Chin-Chun Lu
    • , Karen Miller
    • , Wei Fang
    • , Nai-Yu Wang
    • , Derek Nguyen
    • , Jack Houston
    • , Gilles Carmel
    • , Tam Tran
    • , Mariko Riley
    • , Svetlana Gaidarova
    • , Shuichan Xu
    • , Alexander L. Ruchelman
    • , James Carmichael
    • , Thomas O. Daniel
    • , Brian E. Cathers
    • , Antonia Lopez-Girona
    •  & Philip P. Chamberlain
  2. Department of Nanoparticle Translational Research, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan

    • Takumi Ito
    •  & Hiroshi Handa
  3. The Scripps Research Institute, San Diego, California 92121, USA

    • Lyn’Al Nosaka
    •  & Gabriel C. Lander


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M.E.M., P.P.C., B.P, W.F., J.H., T.I., G.C., and M.R. performed biochemical and crystallographic structural studies. G.L., C.-C.L., K.M., N.-Y.W., D.N., T.T., S.G., and S.X. performed molecular and cellular biology experiments. G.C.L, L.N., M.E.M, and P.P.C. performed electron microscopy studies. A.L.R. performed chemical synthesis. M.E.M., G.L., A.L.-G., J.C., T.I., H.H., T.O.D., B.C., and P.P.C. planned the work, and all authors contributed to the manuscript.

Competing interests

All authors are or have been employees or collaborators of Celgene.

Corresponding authors

Correspondence to Gang Lu or Philip P. Chamberlain.

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