Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation.

Proteolysis Targeting Chimeras (PROTACs), an emerging therapeutic entity designed to degrade target proteins by hijacking the ubiquitin-proteasome system, have the potential to revolutionize the healthcare industry. The broad applicability of this protein degradation strategy has been verified with a few E3 ligases and a variety of distinct targets through the construction of modular chimeric structures. Despite recent efforts to promote the use of PROTACs for clinical applications, most PROTACs do not make it beyond the preclinical stage of drug development. There are several reasons that prevent PROTACs from reaching the market, and the inadequate delivery to the target site is one of the most challenging hurdles. With the increasing need for accelerating the translational process, combining the concepts of PROTACs and delivery systems has been explored to enhance the in vivo performance of PROTACs. These improved delivery strategies can eliminate unfavorable physicochemical properties of PROTACs, improve their targetability, and decrease their off-target side effects. The integration of powerful PROTACs and versatile delivery systems will inaugurate a burgeoning orientation for the field of targeted protein degradation. In this review, we will survey the latest progress in improving the in vivo degradation efficacy of PROTACs through delivery strategies, outline design principles for PROTAC-based delivery systems, discuss the current challenges with PROTACs, and outlook future opportunities in this field.

Development of Substituted Phenyl Dihydrouracil as the Novel Achiral Cereblon Ligands for Targeted Protein Degradation.

Glutarimides such as thalidomide, pomalidomide, and lenalidomide are the most frequently used ligands to recruit E3 ubiquitin ligase cereblon (CRBN) for the development of proteolysis-targeting chimeras (PROTACs). Due to the rapid and spontaneous racemization of glutarimides, most CRBN-recruiting PROTACs are synthesized as a mixture of racemates or diastereomers. Since the (S)-enantiomer is primarily responsible for binding to CRBN, the existence of the largely inactive (R)-enantiomer complicates the drug development process. Herein, we report that substituted achiral phenyl dihydrouracil (PDHU) can be used as a novel class of CRBN ligands for the development of PROTACs. Although the parent PDHU has a minimal binding affinity to CRBN, we found that some substituted PDHUs had a comparable binding affinity to lenalidomide. Structural modeling provided a further understanding of the molecular interactions between PDHU ligands and CRBN. PDHUs also have greater stability than lenalidomide. Finally, potent BRD4 degraders were developed by employing trisubstituted PDHUs.

Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries.

Proteolysis targeting chimeras (PROTACs) have gained tremendous interest in both the academic and pharmaceutical communities. This opens a new way to regulate the cellular protein homeostasis, especially for disease-related proteins. In this work, we designed and synthesized a series of MDM2 degraders based on ligands that were readily prepared by a four-component Ugi reaction. After extensive optimization based on anti-proliferation and MDM2 degradation, WB214 was identified as the most potent anti-proliferative agent in various leukemia cell lines. Surprisingly, our mechanistic investigations indicated that WB214 not only effectively induced the degradation of MDM2, but also led to the degradation of p53. Further studies revealed that WB214 degraded MDM2 as a molecular glue. WB214 and its related analogues did not bind to MDM2 in the p53 binding region and MDM2 was discovered as a novel neo-substrate of the E3 ligase cereblon. Finally, we found that WB214 could potently degrade GSPT1, which could rationalize the inhibition of cell growth. A selective degrader for GSPT1 over MDM2 was then developed through systematically varying different motifs.