The field of PROTACs has taken off in recent years, as the first candidates move through clinical studies.1 It is a little-remembered fact that the first PROTAC was based upon a peptide. The conjugation of the phosphospeptide degron for IκBα linked via an aminosuberone spacer to ovalicinol yielded a molecule that effectively degraded METAP2. Similarly, peptide recognition drove the discovery of degraders of FKBP, the estrogen receptor and PI3 kinase. Two of the most prominent “small molecule” ligands for E3 ligases (VHL-32 and LCL-161) are built around peptidomimetic ligands. The lesson is that peptide sequences are the natural starting points for PROTAC development, and that peptide and peptidomimetic drug design strategies have actually underpinned the development of many reported PROTACs.
We have set out to create a highly efficient and adaptable approach to PROTAC synthesis built upon solid phase methods which allows for rapid synthesis in high yield and minimal purification. Pivotal to these methods are the inclusion of varied points of attachment to the solid support allowing for late stage diversification of any part of the target compound. These approaches will be exemplified by the description of known and novel BET bromodomain targeting PROTACs, which are bone fide anti-cancer targets, as well as highlighting other PROTAC targets under investigation.