Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010).
Kronke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2014).
Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309 (2014).
Kronke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523, 183–188 (2015).
Winter, G. E. et al. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381 (2015).
Lu, J. et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol. 22, 755–763 (2015).
Nowak, R. P. et al. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 14, 706–714 (2018).
Donovan, K. A. et al. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. eLife 7, e38430 (2018).
Matyskiela, M. E. et al. SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate. Nat. Chem. Biol. 14, 981–987 (2018).
Oleinikovas, V., Gainza, P., Ryckmans, T., Fasching, B. & Thoma, N. H. From thalidomide to rational molecular glue design for targeted protein degradation. Annu. Rev. Pharmacol. Toxicol. 64, 291–312 (2024).
Sasso, J. M. et al. Molecular glues: the adhesive connecting targeted protein degradation to the clinic. Biochemistry 62, 601–623 (2023).
Ichikawa, S. et al. The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron. Nature 610, 775–782 (2022).
Beyett, T. S. et al. Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors. Nat. Commun. 13, 2530 (2022).
Schoepfer, J. et al. Discovery of asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1. J. Med. Chem. 61, 8120–8135 (2018).
Liu, J. & Nussinov, R. The role of allostery in the ubiquitin-proteasome system. Crit. Rev. Biochem. Mol. Biol. 48, 89–97 (2013).
Watson, E. R. et al. Molecular glue CELMoD compounds are regulators of cereblon conformation. Science 378, 549–553 (2022).
Orlicky, S. et al. An allosteric inhibitor of substrate recognition by the SCFCdc4 ubiquitin ligase. Nat. Biotechnol. 28, 733–737 (2010).
Petzold, G., Fischer, E. S. & Thoma, N. H. Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase. Nature 532, 127–130 (2016).
Hulme, E. C. & Trevethick, M. A. Ligand binding assays at equilibrium: validation and interpretation. Br. J. Pharmacol. 161, 1219–1237 (2010).
Christopoulos, A. & Kenakin, T. G protein-coupled receptor allosterism and complexing. Pharmacol. Rev. 54, 323–374 (2002).
Fischer, E. S. et al. Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49–53 (2014).
Chamberlain, P. P. et al. Structure of the human cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat. Struct. Mol. Biol. 21, 803–809 (2014).
Martinez Molina, D. et al. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science 341, 84–87 (2013).
Groisman, R. et al. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell 113, 357–367 (2003).
Ohtake, F. et al. Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature 446, 562–566 (2007).
Riching, K. M. et al. Quantitative live-cell kinetic degradation and mechanistic profiling of PROTAC mode of action. ACS Chem. Biol. 13, 2758–2770 (2018).
Miyamoto, D. K. et al. Design and development of IKZF2 and CK1α dual degraders. J. Med. Chem. 66, 16953–16979 (2023).
Park, S. M. et al. Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells. Cancer Cell 41, 726–739 (2023).
Razumkov, H. et al. Discovery of CRBN-dependent WEE1 molecular glue degraders from a multicomponent combinatorial library. J. Am. Chem. Soc. 146, 31433–31443 (2024).
Ting, P. Y. et al. A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction. Science 385, 91–99 (2024).
Russell, P. & Nurse, P. Negative regulation of mitosis by wee1+, a gene encoding a protein kinase homolog. Cell 49, 559–567 (1987).
Schwinn, M. K. et al. CRISPR-mediated tagging of endogenous proteins with a luminescent peptide. ACS Chem. Biol. 13, 467–474 (2018).
Sievers, Q. L. et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362, eaat0572 (2018).
Słabick, M. et al. Expanding the druggable zinc-finger proteome defines properties of drug-induced degradation. Mol. Cell 85, 3184–3201.e14 (2025).
Lindner, S. et al. Chemical inactivation of the E3 ubiquitin ligase cereblon by pomalidomide-based homo-PROTACs. J. Vis. Exp. 147, e59472 (2019).
Ichikawa, S. et al. The cyclimids: degron-inspired cereblon binders for targeted protein degradation. Cell Chem. Biol. 31, 1162–1175 (2024).
Donovan, K. A. et al. Mapping the degradable kinome provides a resource for expedited degrader development. Cell 183, 1714–1731 (2020).
Petzold, G. et al. Mining the CRBN target space redefines rules for molecular glue–induced neosubstrate recognition. Science 389, eadt6736 (2025).
Conn, P. J., Christopoulos, A. & Lindsley, C. W. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8, 41–54 (2009).
Wang, J., Gareri, C. & Rockman, H. A. G-protein-coupled receptors in heart disease. Circ. Res. 123, 716–735 (2018).
Adrian, F. J. et al. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat. Chem. Biol. 2, 95–102 (2006).
Wylie, A. A. et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature 543, 733–737 (2017).
