PROTAC cell permeability and oral bioavailability: a journey into uncharted territory

References

• 1. Edmondson SD, Yang B, Fallan C. Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: recent progress and future challenges. Bioorg. Med. Chem. Lett. 29, 1555–1564 (2019).
  Medline CASGoogle Scholar
• 2. Maple HJ, Clayden N, Baron A, Stacey C, Felix R. Developing degraders: principles and perspectives on design and chemical space. Med. Chem. Commun. 10, 1755–1764 (2019).
  CASGoogle Scholar
• 3. Doak BC, Over B, Giordanetto F, Kihlberg J. Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates. Chem. Biol. 21, 1115–1142 (2014).
  Medline CASGoogle Scholar
• 4. DeGoey DA, Chen H-J, Cox PB, Wendt MD. Beyond the rule of 5: lessons learned from AbbVie's drugs and compound collection. J. Med. Chem. 61, 2636–2651 (2018).
  Medline CASGoogle Scholar
• 5. Wishart DS, Feunang YD, Guo AC et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 46, D1074–D1082 (2018).
  Medline CASGoogle Scholar
• 6. Weng G, Shen C, Cao D et al. PROTAC-DB: an online database of PROTACs. Nucleic Acids Res. 49(D1), D1381–D1387 (2021).
  Medline CASGoogle Scholar
• 7. Atilaw Y, Poongavanam V, Svensson Nilsson C et al. Solution conformations shed light on PROTAC cell permeability. ACS Med. Chem. Lett. 12, 107–114 (2021).
  Medline CASGoogle Scholar
• 8. Danelius E, Poongavanam V, Peintner S, Wieske LHE, Erdélyi M, Kihlberg J. Solution conformations explain the chameleonic behavior of macrocyclic drugs. Chem. Eur. J. 26(23), 5231–5244 (2020).
  Medline CASGoogle Scholar
• 9. Klein VG, Townsend CE, Testa A et al. Understanding and improving the membrane permeability of VH032-based PROTACs. ACS Med. Chem. Lett. 11(9), 1732–1738 (2020).
  Medline CASGoogle Scholar
• 10. Pike A, Williamson B, Harlfinger S, Martin S, McGinnity DF. Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective. Drug Discov. Today 25, 1793-1800 (2020).
  Medline CASGoogle Scholar
• 11. Cantrill C, Chaturvedi P, Rynn C, Schaffland JP, Walter I, Wittwer MB. Fundamental aspects of DMPK optimization of targeted protein degraders. Drug Discov. Today 25, 969–982 (2020).
  Medline CASGoogle Scholar
• 12. Ermondi G, Vallaro M, Caron G. Degraders early developability assessment: face-to-face with molecular properties. Drug Discov. Today 25(9), 1585–1591 (2020).
  Medline CASGoogle Scholar
• 13. Scott DE, Rooney TPC, Bayle ED et al. Systematic investigation of the permeability of androgen receptor PROTACs. ACS Med. Chem. Lett. 11, 1539–1547 (2020).
  Medline CASGoogle Scholar
• 14. Halford B. Arvinas unveils PROTAC structures. Chem. Eng. News 99(14), magazine/99/09914 (2021).
  Google Scholar
• 15. Sun X, Wang J, Yao X et al. A chemical approach for global protein knockdown from mice to non-human primates. Cell Discov. 5, 10 (2019).
  MedlineGoogle Scholar
• 16. Tinworth CP, Lithgow H, Dittus L et al. PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding. ACS Chem. Biol. 14, 342–347 (2019).
  Medline CASGoogle Scholar
• 17. Poongavanam V, Danelius E, Peintner S et al. Conformational sampling of macrocyclic drugs in different environments – can we find the relevant conformations? ACS Omega 3, 11742–11757 (2018).
  Medline CASGoogle Scholar
• 18. Poongavanam V, Atilaw Y, Ye S et al. Predicting the permeability of macrocycles from conformational sampling – limitations of molecular flexibility. J. Pharm. Sci. 110, 301–313 (2021).
  Medline CASGoogle Scholar
• 19. Goracci L, Desantis J, Valeri A, Castellani B, Eleuteri M, Cruciani G. Understanding the metabolism of proteolysis targeting chimeras (PROTACs): the next step toward pharmaceutical applications. J. Med. Chem. 63, 11615–11638 (2020).
  Medline CASGoogle Scholar
• 20. Bemis TA, La Clair JJ, Burkart MD. Unraveling the role of linker design in proteolysis targeting chimeras. J. Med. Chem. 64, 8042–8052 (2021).
  Medline CASGoogle Scholar