PROTAC & Targeted Therapeutics

The PROTAC & Targeted Therapeutics core is dedicated to bridge the gap between basic biomedical science research at UF and therapeutic discovery. We utilize targeted protein degradation (TPD) by proteolysis-targeting chimera (PROTAC) as a platform to develop innovative drug candidates and tool molecules for biological studies. Academic labs play an important role in driving the innovation and technology translation in drug discovery and development, especially in the area of identification and characterization of novel potential therapeutic targets. However, many biomedical labs lack the expertise and proper set-ups to initiate drug discovery campaigns for the eventual clinical translation. In addition, many desirable protein targets are considered to be ‘undruggable’, ‘difficult-to-drug’, or ‘under-drugged’, including targets that play scaffolding functions, are transcription factors, are difficult to achieve isoform selectivity by traditional small molecule inhibitors (SMIs), lack a functional binding pocket, and cause on-target toxicity with SMIs. We believe the emerging PROTAC technology could be utilized to address these challenges in drug discovery. In collaboration with other cores in the CNPD3, we can provide service in 1) drug discovery — design, synthesis, and initial evaluation of PROTAC molecules with proper target ligand, E3 ligase ligand and linker unit; 2) assist in target selection, hit/lead identification and characterization; 3) chemical genetics — develop PROTAC probes to knockdown proteins of interest.

PROTACs are bivalent small-molecules containing a pharmacophoric unit that recognizes the target protein linked to a second pharmacophoric unit that binds to a specific E3 ubiquitin ligase complex. Such molecules can recruit the target protein to the E3 ligase complex, promote proximity-induced ubiquitination of the target protein, and lead to its degradation through the ubiquitin-proteasome system (UPS). PROTACs act catalytically to induce targeted protein degradation in a sub-stoichiometric manner and their effect is not limited by equilibrium occupancy. In addition, PROTACs deplete protein levels rather than transiently block an active site, resulting in a more pronounced and longer-lasting disruption of protein function compared with the conventional SMIs. Therefore, PROTACs are intrinsically more efficacious than traditional occupancy-driven protein inhibitors. It has also been demonstrated that target depletion selectivity by PROTACs can substantially exceed the binding selectivity of their corresponding parent target protein ligands. Thus, PROTAC approach has the potential to turn a nonselec­tive or promiscuous ligands into more selective degraders, which can reduce off-target toxicity. In addition, the ligand that binds to the target protein is not required to have the inhibitory function for a PROTAC to function as a degrader; any form of engagement with the target protein could potentially induce degradation. Thus, using the PROTAC approach may improve the chance of finding protein inhibitors and have the potential of targeting those ‘undruggable’ or ‘difficult-to-drug’ protein targets. Moreover, because PROTACs rely on E3 ligases to induce protein degradation, it is possible for them to achieve cell/tissue selectivity even when their target proteins are ubiquitously expressed, if they target an E3 ligase that is differentially expressed in different cells or tissues. Numerous PROTACs that are superior to their corresponding occupancy-driven protein inhibitors, both in vitro and in vivo, have been identified and to date, more than a dozen have entered clinical trials, highlighting the promise of this technology.

Core Director