Challenges and Opportunities for In Vivo PROTAC Delivery

Future Medicinal ChemistryVol. 14, No. 3 EditorialChallenges and opportunities for in vivo PROTAC deliveryAndrew B Benowitz, Paul T Scott-Stevens & John D HarlingAndrew B Benowitz *Author for correspondence: E-mail Address: andrew.b.benowitz@GSK.comhttps://orcid.org/0000-0002-9913-605XMedicine Design, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK, Paul T Scott-StevensIn Vitro/In Vivo Translation, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK & John D HarlingMedicine Design, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UKPublished Online:16 Sep 2021https://doi.org/10.4155/fmc-2021-0223AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: chameleonicityoral exposureparenteral deliveryPROTACReferences1. Nalawansha DA, Crews CM. PROTACs: an emerging therapeutic modality in precision medicine. Cell Chem. Biol. 27(8), 998–1014 (2020).Crossref, Medline, CAS, Google Scholar2. Veber DF, Johnson SR, Cheng H-Y, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 45(12), 2615–2623 (2002).Crossref, Medline, CAS, Google Scholar3. Lee GT, Nagaya N, Desantis J et al. Effects of MTX-23, a novel PROTAC of androgen receptor splice variant-7 and androgen receptor, on CRPC resistant to second-line antiandrogen therapy. Mol. Cancer Ther. 20(3), 490–499 (2021).Crossref, Medline, CAS, Google Scholar4. Luo G, Li Z, Lin X et al. Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo. Acta Pharm. Sin. B 11(5), 1300–1314 (2021).Crossref, Medline, CAS, Google Scholar5. Whitty A, Zhong M, Viarengo L, Beglov D, Hall DR, Vajda S. Quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugs. Drug Discov. Today 21(5), 712–717 (2016).Crossref, Medline, CAS, Google Scholar6. Atilaw Y, Poongavanam V, Svensson Nilsson C et al. Solution conformations shed light on PROTAC cell permeability. ACS Med. Chem. Lett. 12(1), 107–114 (2021).Crossref, Medline, CAS, Google Scholar7. David L, Wenlock M, Barton P, Ritzén A. Prediction of chameleonic efficiency. ChemMedChem 16(17), 2669–2685 (2021).Crossref, Medline, CAS, Google Scholar8. Ermondi G, Garcia Jimenez D, Rossi Sebastiano M, Caron G. Rational control of molecular properties is mandatory to exploit the potential of PROTACs as oral drugs. ACS Med. Chem. Lett. 12(7), 1056–1060 (2021).Crossref, Medline, CAS, Google Scholar9. Hodge D, Back DJ, Gibbons S, Khoo SH, Marzolini C. Pharmacokinetics and drug–drug interactions of long-acting intramuscular cabotegravir and rilpivirine. Clin. Pharmacokinet. 60(7), 835–853 (2021).Crossref, Medline, CAS, Google Scholar10. Miah AH, Smith IED, Rackham M et al. Optimization of a series of RIP2 PROTACs. J. Med. Chem. 64(17), 12978–13003 (2021).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited BySpecial Focus Issue – Targeted protein degradation: a new paradigm in medicinal chemistryHarriet Wall26 January 2022 | Future Medicinal Chemistry, Vol. 14, No. 3 Vol. 14, No. 3 Follow us on social media for the latest updates Metrics Downloaded 913 times History Received 2 August 2021 Accepted 1 September 2021 Published online 16 September 2021 Published in print February 2022 Information© 2021 Newlands PressKeywordschameleonicityoral exposureparenteral deliveryPROTACFinancial & competing interests disclosureThe authors are employees and/or shareholders of GlaxoSmithKline. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download