1932

Abstract

Thalidomide and its derivatives are powerful cancer therapeutics that are among the best-understood molecular glue degraders (MGDs). These drugs selectively reprogram the E3 ubiquitin ligase cereblon (CRBN) to commit target proteins for degradation by the ubiquitin-proteasome system. MGDs create novel recognition interfaces on the surface of the E3 ligase that engage in induced protein-protein interactions with neosubstrates. Molecular insight into their mechanism of action opens exciting opportunities to engage a plethora of targets through a specific recognition motif, the G-loop. Our analysis shows that current CRBN-based MGDs can in principle recognize over 2,500 proteins in the human proteome that contain a G-loop. We review recent advances in tuning the specificity between CRBN and its MGD-induced neosubstrates and deduce a set of simple rules that govern these interactions. We conclude that rational MGD design efforts will enable selective degradation of many more proteins, expanding this therapeutic modality to more disease areas.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-022123-104147
2024-01-23
2024-12-07
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/64/1/annurev-pharmtox-022123-104147.html?itemId=/content/journals/10.1146/annurev-pharmtox-022123-104147&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Silverman WA. 2002. The schizophrenic career of a “monster drug. .” Pediatrics 110:2404–6
    [Google Scholar]
  2. 2.
    Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G. 1991. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J. Exp. Med. 173:3699–703
    [Google Scholar]
  3. 3.
    D'Amato RJ, Loughnan MS, Flynn E, Folkman J. 1994. Thalidomide is an inhibitor of angiogenesis. PNAS 91:94082–85
    [Google Scholar]
  4. 4.
    Siegel DS, Schiller GJ, Song KW, Agajanian R, Stockerl-Goldstein K et al. 2020. Pomalidomide plus low-dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure. Br. J. Haematol. 188:4501–10
    [Google Scholar]
  5. 5.
    Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN et al. 2014. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343:6168301–5
    [Google Scholar]
  6. 6.
    Lu G, Middleton RE, Sun H, Naniong M, Ott CJ et al. 2014. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:6168305–9
    [Google Scholar]
  7. 7.
    Krönke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN et al. 2015. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523:7559183–88
    [Google Scholar]
  8. 8.
    Sievers QL, Petzold G, Bunker RD, Renneville A, Słabicki M et al. 2018. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362:6414eaat0572
    [Google Scholar]
  9. 9.
    Cao S, Kang S, Mao H, Yao J, Gu L, Zheng N. 2022. Defining molecular glues with a dual-nanobody cannabidiol sensor. Nat. Commun. 13:1815
    [Google Scholar]
  10. 10.
    Han T, Goralski M, Gaskill N, Capota E, Kim J et al. 2017. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356:6336eaal3755
    [Google Scholar]
  11. 11.
    Shergalis AG, Marin VL, Rhee DY, Senaweera S, McCloud RL et al. 2023. CRISPR screen reveals BRD2/4 molecular glue-like degrader via recruitment of DCAF16. ACS Chem. Biol. 18:2331–39
    [Google Scholar]
  12. 12.
    Bradner J. 2021. Molecular glues for intractable targets Dana-Farber Cancer Inst. Target. Protein Degrad. Semin. Febr. 4. https://youtu.be/eDZ8UHi1EhI?t=1
    [Google Scholar]
  13. 13.
    Słabicki M, Kozicka Z, Petzold G, Li Y-D, Manojkumar M et al. 2020. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature 585:7824293–97
    [Google Scholar]
  14. 14.
    Kramer LT, Zhang X. 2022. Expanding the landscape of E3 ligases for targeted protein degradation. Curr. Res. Chem. Biol. 2:100020
    [Google Scholar]
  15. 15.
    Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y et al. 2014. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN. Br. J. Haematol. 164:6811–21
    [Google Scholar]
  16. 16.
    Petzold G, Fischer ES, Thomä NH. 2016. Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase. Nature 532:7597127–30
    [Google Scholar]
  17. 17.
    Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu C-C et al. 2016. A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase. Nature 535:7611252–57
    [Google Scholar]
  18. 18.
    DuPai CD, Davies BW, Wilke CO. 2021. A systematic analysis of the beta hairpin motif in the Protein Data Bank. Protein Sci. 30:3613–23
    [Google Scholar]
  19. 19.
    Matyskiela ME, Clayton T, Zheng X, Mayne C, Tran E et al. 2020. Crystal structure of the SALL4-pomalidomide-cereblon-DDB1 complex. Nat. Struct. Mol. Biol. 27:4319–22
    [Google Scholar]
  20. 20.
    Wang ES, Verano AL, Nowak RP, Yuan JC, Donovan KA et al. 2021. Acute pharmacological degradation of Helios destabilizes regulatory T cells. Nat. Chem. Biol. 17:6711–17
    [Google Scholar]
  21. 21.
    Furihata H, Yamanaka S, Honda T, Miyauchi Y, Asano A et al. 2020. Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide. Nat. Commun. 11:14578
    [Google Scholar]
  22. 22.
    Watson ER, Novick S, Matyskiela ME, Chamberlain PP, de la Peña AH et al. 2022. Molecular glue CELMoD compounds are regulators of cereblon conformation. Science 378:6619549–53
    [Google Scholar]
  23. 23.
    Hanzl A, Casement R, Imrichova H, Hughes SJ, Barone E et al. 2023. Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders. Nat. Chem. Biol. 19:323–33
    [Google Scholar]
  24. 24.
    Shen C, Nayak A, Neitzel LR, Adams AA, Silver-Isenstadt M et al. 2021. The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling. Nat. Commun. 12:15263
    [Google Scholar]
  25. 25.
    Ichikawa S, Flaxman HA, Xu W, Vallavoju N, Lloyd HC et al. 2022. The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron. Nature 610:7933775–82
    [Google Scholar]
  26. 26.
    Gainza P, Wehrle S, Van Hall-Beauvais A, Marchand A, Scheck A et al. 2023. De novo design of site-specific protein interactions with learned surface fingerprints. Nature 617:7959176–84
    [Google Scholar]
  27. 27.
    Donovan KA, An J, Nowak RP, Yuan JC, Fink EC et al. 2018. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. eLife 7:e38430
    [Google Scholar]
  28. 28.
    Jumper J, Evans R, Pritzel A, Green T, Figurnov M et al. 2021. Highly accurate protein structure prediction with AlphaFold. Nature 596:7873583–89
    [Google Scholar]
  29. 29.
    Tunyasuvunakool K, Adler J, Wu Z, Green T, Zielinski M et al. 2021. Highly accurate protein structure prediction for the human proteome. Nature 596:7873590–96
    [Google Scholar]
  30. 30.
    Yamanaka S, Horiuchi Y, Matsuoka S, Kido K, Nishino K et al. 2022. A proximity biotinylation-based approach to identify protein-E3 ligase interactions induced by PROTACs and molecular glues. Nat. Commun. 13:1183
    [Google Scholar]
  31. 31.
    Asatsuma-Okumura T, Ando H, de Simone M, Yamamoto J, Sato T et al. 2019. p63 is a cereblon substrate involved in thalidomide teratogenicity. Nat. Chem. Biol. 15:111077–84
    [Google Scholar]
  32. 32.
    Matyskiela ME, Zhu J, Baughman JM, Clayton T, Slade M et al. 2020. Cereblon modulators target ZBTB16 and its oncogenic fusion partners for degradation via distinct structural degrons. ACS Chem. Biol. 15:123149–58
    [Google Scholar]
  33. 33.
    Dunbar K, Macartney TJ, Sapkota GP. 2021. IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling. Life Sci. Alliance 4:2e202000804
    [Google Scholar]
  34. 34.
    Renneville A, Gasser JA, Grinshpun DE, Jean Beltran PM, Udeshi ND et al. 2021. Avadomide induces degradation of ZMYM2 fusion oncoproteins in hematologic malignancies. Blood Cancer Discov. 2:3250–65
    [Google Scholar]
  35. 35.
    Jan M, Scarfò I, Larson RC, Walker A, Schmidts A et al. 2021. Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide. Sci. Transl. Med. 13:575eabb6295
    [Google Scholar]
  36. 36.
    Teng M, Lu W, Donovan KA, Sun J, Krupnick NM et al. 2022. Development of PDE6D and CK1α degraders through chemical derivatization of FPFT-2216. J. Med. Chem. 65:1747–56
    [Google Scholar]
  37. 37.
    Nguyen TM, Deb A, Kokkonda P, Sreekanth V, Tiwari PK et al. 2021. Proteolysis targeting chimeras with reduced off-targets. bioRxiv 2021.11.18.468552. https://doi.org/10.1101/2021.11.18.468552
  38. 38.
    Hansen JD, Correa M, Alexander M, Nagy M, Huang D et al. 2021. CC-90009: a cereblon E3 ligase modulating drug that promotes selective degradation of GSPT1 for the treatment of acute myeloid leukemia. J. Med. Chem. 64:41835–43
    [Google Scholar]
  39. 39.
    Gavory G, Ghandi M, d'Alessandro A-C, Bonenfant D, Chicas A et al. 2022. Identification of MRT-2359 a potent, selective and orally bioavailable GSPT1-directed molecular glue degrader (MGD) for the treatment of cancers with Myc-induced translational addiction. Cancer Res. 82:Suppl. 123929 Abstr. )
    [Google Scholar]
  40. 40.
    Gavory G, Fasching B, Bonenfant D, Sadok A, Singh A et al. 2021. Identification of GSPT1-directed molecular glue degrader (MGD) for the treatment of Myc-driven breast cancer. Mol. Cancer Ther. 20:Suppl. 12LBA004 Abstr. )
    [Google Scholar]
  41. 41.
    Janzen DM. 2004. The effect of eukaryotic release factor depletion on translation termination in human cell lines. Nucleic Acids Res. 32:154491–502
    [Google Scholar]
  42. 42.
    Kazantsev A, Krasavin M. 2022. Ligands for cereblon: 2017–2021 patent overview. Expert Opin. Ther. Pat. 32:2171–90
    [Google Scholar]
  43. 43.
    Ishoey M, Chorn S, Singh N, Jaeger MG, Brand M et al. 2018. Translation termination factor GSPT1 is a phenotypically relevant off-target of heterobifunctional phthalimide degraders. ACS Chem. Biol. 13:3553–60
    [Google Scholar]
  44. 44.
    Yang Z, Sun Y, Ni Z, Yang C, Tong Y et al. 2021. Merging PROTAC and molecular glue for degrading BTK and GSPT1 proteins concurrently. Cell Res. 31:121315–18
    [Google Scholar]
  45. 45.
    Fischer Lab 2020. Fischer lab's proteomics database Database, Dana-Farber Cancer Inst. Boston, MA: https://proteomics.fischerlab.org
    [Google Scholar]
  46. 46.
    Lier S, Sellmer A, Orben F, Heinzlmeir S, Krauß L et al. 2022. A novel cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer. Bioorg. Chem. 119:105505
    [Google Scholar]
  47. 47.
    Yang J, Li Y, Aguilar A, Liu Z, Yang C-Y, Wang S. 2019. Simple structural modifications converting a bona fide MDM2 PROTAC degrader into a molecular glue molecule: a cautionary tale in the design of PROTAC degraders. J. Med. Chem. 62:219471–87
    [Google Scholar]
  48. 48.
    Powell CE, Du G, Che J, He Z, Donovan KA et al. 2020. Selective degradation of GSPT1 by cereblon modulators identified via a focused combinatorial library. ACS Chem. Biol. 15:102722–30
    [Google Scholar]
  49. 49.
    Nishiguchi G, Keramatnia F, Min J, Chang Y, Jonchere B et al. 2021. Identification of potent, selective, and orally bioavailable small-molecule GSPT1/2 degraders from a focused library of cereblon modulators. J. Med. Chem. 64:117296–311
    [Google Scholar]
  50. 50.
    Zou J, Jones RJ, Wang H, Kuiatse I, Shirazi F et al. 2020. The novel protein homeostatic modulator BTX306 is active in myeloma and overcomes bortezomib and lenalidomide resistance. J. Mol. Med. 98:81161–73
    [Google Scholar]
  51. 51.
    Nowak RP, Che J, Ferrao S, Kong NR, Liu H et al. 2023. Structural rationalization of GSPT1 and IKZF1 degradation by thalidomide molecular glue derivatives. RSC Med. Chem. 14:501–6
    [Google Scholar]
  52. 52.
    Gemechu Y, Millrine D, Hashimoto S, Prakash J, Sanchenkova K et al. 2018. Humanized cereblon mice revealed two distinct therapeutic pathways of immunomodulatory drugs. PNAS 115:4611802–7
    [Google Scholar]
  53. 53.
    Burslem GM, Ottis P, Jaime-Figueroa S, Morgan A, Cromm PM et al. 2018. Efficient synthesis of immunomodulatory drug analogues enables exploration of structure-degradation relationships. ChemMedChem 13:151508–12
    [Google Scholar]
  54. 54.
    de Wispelaere M, Du G, Donovan KA, Zhang T, Eleuteri NA et al. 2019. Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations. Nat. Commun. 10:13468
    [Google Scholar]
  55. 55.
    Matyskiela ME, Zhang W, Man H-W, Muller G, Khambatta G et al. 2018. A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos. J. Med. Chem. 61:2535–42
    [Google Scholar]
  56. 56.
    Chamberlain PP, D'Agostino LA, Ellis JM, Hansen JD, Matyskiela ME et al. 2019. Evolution of cereblon-mediated protein degradation as a therapeutic modality. ACS Med. Chem. Lett. 10:121592–602
    [Google Scholar]
  57. 57.
    Nowak RP, DeAngelo SL, Buckley D, He Z, Donovan KA et al. 2018. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 14:7706–14
    [Google Scholar]
  58. 58.
    Sperling AS, Burgess M, Keshishian H, Gasser JA, Bhatt S et al. 2019. Patterns of substrate affinity, competition, and degradation kinetics underlie biological activity of thalidomide analogs. Blood 134:2160–70
    [Google Scholar]
  59. 59.
    Yu HH, Reitsma JM, Sweredoski MJ, Moradian A, Hess S, Deshaies RJ. 2019. Single subunit degradation of WIZ, a lenalidomide- and pomalidomide-dependent substrate of E3 ubiquitin ligase CRL4CRBN. bioRxiv 595389. https://doi.org/10.1101/595389
  60. 60.
    Li L, Xue W, Shen Z, Liu J, Hu M et al. 2020. A cereblon modulator CC-885 induces CRBN- and p97-dependent PLK1 degradation and synergizes with volasertib to suppress lung cancer. Mol. Ther. Oncolytics 18:215–25
    [Google Scholar]
  61. 61.
    Hao B, Li X, Jia X, Wang Y, Zhai L et al. 2020. The novel cereblon modulator CC-885 inhibits mitophagy via selective degradation of BNIP3L. Acta Pharmacol. Sin. 41:91246–54
    [Google Scholar]
  62. 62.
    Tochigi T, Miyamoto T, Hatakeyama K, Sakoda T, Ishihara D et al. 2020. Aromatase is a novel neosubstrate of cereblon responsible for immunomodulatory drug-induced thrombocytopenia. Blood 135:242146–58
    [Google Scholar]
  63. 63.
    Yamamoto J, Suwa T, Murase Y, Tateno S, Mizutome H et al. 2020. ARID2 is a pomalidomide-dependent CRL4CRBN substrate in multiple myeloma cells. Nat. Chem. Biol. 16:111208–17
    [Google Scholar]
  64. 64.
    Surka C, Jin L, Mbong N, Lu C-C, Jang IS et al. 2021. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells. Blood 137:5661–77
    [Google Scholar]
  65. 65.
    Zhao M, Hu M, Chen Y, Liu H, Chen Y et al. 2021. Cereblon modulator CC-885 induces CRBN-dependent ubiquitination and degradation of CDK4 in multiple myeloma. Biochem. Biophys. Res. Commun. 549:150–56
    [Google Scholar]
  66. 66.
    Lin Z, Shen D, Yang B, Woo CM. 2022. Molecular and structural characterization of lenalidomide-mediated sequestration of eIF3i. ACS Chem. Biol. 17:113229–37
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-022123-104147
Loading
/content/journals/10.1146/annurev-pharmtox-022123-104147
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error