Identification of a primary target of thalidomide teratogenicity

Integrated Research Institute, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
Science (Impact Factor: 31.48). 03/2010; 327(5971):1345-50. DOI: 10.1126/science.1177319
Source: PubMed

ABSTRACT Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.

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Available from: Hiroshi Handa, Aug 29, 2015
    • "This robust accumulation of BRD4, together with the reversible nature of inhibitor binding to BRD4, may in part account for the modest effect of these inhibitors on downstream c-MYC suppression and cell proliferation inhibition. To circumvent these limitations, we designed a hetero-bifunctional molecule , ARV-825, by connecting a small-molecule BRD4 binding moiety (OTX015) to an E3 ligase cereblon binding moiety (pomalidomide ) using PROTAC technology (Boi et al., 2015; Fischer et al., 2014; Ito et al., 2010). OTX015 is currently in phase I clinical trials and pomalidomide is a potent third-generation immunomodulatory drug (IMiD), which functions through interacting with the E3 ligase cereblon and inducing degradation of essential Ikaros transcription factors in MM (Boi et al., 2015; Lu et al., 2014). "
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    ABSTRACT: BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small-molecule BRD4 inhibitors, resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small-molecule inhibitors. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Chemistry & biology 06/2015; DOI:10.1016/j.chembiol.2015.05.009 · 6.59 Impact Factor
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    • "The evidence is not merely circumstantial. Teratogenic drugs that disrupt the development of limb buds (e.g., thalidomide) result in malformation or complete absence of limbs (Ito et al., 2010). The earlier structure is necessary for development of the later structure. "
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    • "Recently, the crystal structure of DDB1-CRBN E3 ubiquitin ligase in complex with THAL/LEN has been described [13] [14]. CBMs bind at the C terminus of CRBN in a small hydrophobic pocket composed of three tryptophan residues (Trp380, Trp386 and Trp400) [13] and mutations in these residues have been demonstrated to cause CBM resistance [2] [10] [15]. This thalidomide binding domain (TBD) is highly conserved across species, however four amino acids differ between mouse and human proteins, most likely explaining lack of rodent responsiveness to IMiDs [13]. "
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    ABSTRACT: Immunomodulation is an established treatment strategy in Multiple Myeloma with Thalidomide and its derivatives Lenalidomide and Pomalidomide as its FDA approved representatives. Just recently the method of action of these cereblon binding molecules was deciphered and results from large phase 3 trials confirmed the backbone function of this drug family in various combination therapies. This review details the to-date knowledge concerning mechanism of IMiD action, clinical applications and plausible escape mechanisms in which cells may become resistant/refractory to cereblon binding molecule based treatment.
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