Proteolysis targeting chimeras (PROTACs) in 'beyond rule-of-five' chemical space: Recent progress and future challenges

Scott D Edmondson; Bin Yang; Charlene Fallan

doi:10.1016/j.bmcl.2019.04.030

Proteolysis targeting chimeras (PROTACs) in 'beyond rule-of-five' chemical space: Recent progress and future challenges

Bioorg Med Chem Lett. 2019 Jul 1;29(13):1555-1564. doi: 10.1016/j.bmcl.2019.04.030. Epub 2019 Apr 20.

Authors

Scott D Edmondson¹, Bin Yang², Charlene Fallan³

Affiliations

¹ Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Boston, MA, USA. Electronic address: [email protected].
² Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Boston, MA, USA.
³ Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK.

PMID: 31047748
DOI: 10.1016/j.bmcl.2019.04.030

Abstract

Proteolysis targeting chimeras (PROTACs) are heterobifunctional compounds with molecular weights and other properties that lie outside the classic 'rule-of-five' space. Consequently, PROTACs have unique challenges associated with their development as potential therapeutic agents. This review summarizes and analyzes a representative set of recent PROTACs and highlights some of the potential future challenges facing this promising modality.

Keywords: Absorption; Beyond rule-of-five; Degradation; Oral bioavailability; PROTACs; Proteolysis targeting chimeras; bRo5.

Publication types

Review

MeSH terms

Chimera / metabolism*
Drug Discovery / methods*
Humans
Proteolysis