A current bottleneck in the development of proteolysis targeting chimeras (PROTACs) is the empirical nature of linker length structure−activity relationships (SARs). A multidisciplinary approach to alleviate the bottleneck is detailed here. First, we examine four published synthetic approaches that have been developed to increase synthetic throughput. We then discuss advances in structural biology and computational chemistry that have led to successful rational PROTAC design efforts and give promise to de novo linker design in silico. Lastly, we present a model generated from a curated list of linker SARs studies normalized to reflect how linear linker length affects the observed degradation potency (DC 50 ).

Semifluorinated polymer surfactants, composed of a monomethyl poly(ethylene glycol) (mPEG) hydrophilic head group and either 1, 2, or 3 perfluoro-tert-butyl (PFtB) groups as the fluorophilic tail, were synthesized, and their aqueous self-assemblies were investigated as a potential design for theranostic nanoparticles. Polymers with three PFtB groups (PFtBTRI) solely formed stable, spherical micelles, approximately 12 nm in size. These PFtBTRI surfactants demonstrate similar characteristics with those of polymers with linear perfluorocarbon tails, despite large differences in tail structure. For example, PFtB polymer solutions stably emulsified 20 v/v% sevoflurane with perfluorooctyl bromide (PFOB) as a stabilizer. However, these PFtB polymers have the additional potential to serve as F-MRI contrast agents. PFtBTRI micelles gave one narrow 19F-NMR signal in D2O, with T1 and T2 parameters of approximately 500 and 100 ms, respectively. 19F-MR images of PFtB polymer solutions at 1 mM gave intense signal at 4.7 T without sensitizers or selective excitation sequences. These preliminary data demonstrate the potential of PFtB polymers as a basic design, which can be further modified to serve as dual drug-delivery and imaging vehicles.

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Chemoselectivity of the traceless Staudinger ligation was leveraged to enable assembly of chimeric small-molecule linker variants in a one-pot approach.