CRBN binds IMiDs

Stable Identifier
R-HSA-9681169
Type
Reaction [binding]
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
General
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

Immunomodulatory drugs (IMiDs), a new class of anti cancer drug derived from thalidomide, exert potent anti cancer effects. IMiDs bind to cereblon (CRBN), a substrate receptor of CRL4 E3 ligase, to induce the ubiquitination and degradation of IKZF1 and IKZF3 (encoding transcription factors Ikaros and Aiolos) in multiple myeloma cells, contributing to their anti myeloma activity (Ito & Handa 2016, 2019, Asatsuma Okumura et al. 2019).

Thalidomide and anti inflammatory mediator therapy are being evaluated for clinical efficacy in patients with severe COVID-19. These combine the immunosuppressive action of thalidomide with the anti inflammatory actions of glucocorticoids and COX inhibition (clinical trials NCT04273529 and NCT04273581).

Additional thalidomide analogues have activities that suggest possible roles for them in COVID-19 treatments although we have not annotated them here. Pomalidomide and lenalidomide act as immunomodulatory antineoplastic agents. Their primary target is CRBN. They bind to this target and inhibit ubiquitin ligase activity (Lopez Girona et al. 2012). IKZF1 and IKZF3 are susceptibility loci for systemic lupus erythematosus (SLE). Iberdomide (CC 220), a CRBN modulator with higher binding affinity than other IMiDs, targets a greater degradation of Ikaros and Aiolos than other IMiDs (Matyskiela et al. 2018, Schafer et al. 2018). Avadomide, currently in clinical studies, binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B cell lymphoma (DLBCL) (Hagner et al. 2015), advanced solid tumors, non Hodgkin lymphoma (NHL) and multiple myeloma (Rasco et al. 2019).

Literature References
PubMed ID Title Journal Year
26002965 CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL

Hagner, PR, Man, HW, Fontanillo, C, Wang, M, Couto, S, Breider, M, Bjorklund, C, Havens, CG, Lu, G, Rychak, E, Raymon, H, Narla, RK, Barnes, L, Khambatta, G, Chiu, H, Kosek, J, Kang, J, Amantangelo, MD, Waldman, M, Lopez-Girona, A, Cai, T, Pourdehnad, M, Trotter, M, Daniel, TO, Schafer, PH, Klippel, A, Thakurta, A, Chopra, R, Gandhi, AK

Blood 2015
29945920 Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus

Schafer, PH, Ye, Y, Wu, L, Kosek, J, Ringheim, G, Yang, Z, Liu, L, Thomas, M, Palmisano, M, Chopra, R

Ann. Rheum. Dis. 2018
28425720 A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos

Matyskiela, ME, Zhang, W, Man, HW, Muller, G, Khambatta, G, Baculi, F, Hickman, M, LeBrun, L, Pagarigan, B, Carmel, G, Lu, CC, Lu, G, Riley, M, Satoh, Y, Schäfer, P, Daniel, TO, Carmichael, J, Cathers, BE, Chamberlain, PP

J. Med. Chem. 2018
30201761 A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies

Rasco, DW, Papadopoulos, KP, Pourdehnad, M, Gandhi, AK, Hagner, PR, Li, Y, Wei, X, Chopra, R, Hege, K, DiMartino, J, Shih, K

Clin. Cancer Res. 2019
20223979 Identification of a primary target of thalidomide teratogenicity

Ito, T, Ando, H, Suzuki, T, Ogura, T, Hotta, K, Imamura, Y, Yamaguchi, Y, Handa, H

Science 2010
22552008 Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide

Lopez-Girona, A, Mendy, D, Ito, T, Miller, K, Gandhi, AK, Kang, J, Karasawa, S, Carmel, G, Jackson, P, Abbasian, M, Mahmoudi, A, Cathers, B, Rychak, E, Gaidarova, S, Chen, R, Schafer, PH, Handa, H, Daniel, TO, Evans, JF, Chopra, R

Leukemia 2012
Participants
Participant Of
Authored
Reviewed
Created
Cite Us!